G Model

BCP-12143; No. of Pages 10 Biochemical Pharmacology xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Biochemical Pharmacology journal homepage: www.elsevier.com/locate/biochempharm

Commentary

DJ-1 as a human oncogene and potential therapeutic target Ji Cao 1, Siyue Lou 1, Meidan Ying, Bo Yang * Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China

A R T I C L E I N F O

A B S T R A C T

Article history: Received 8 October 2014 Accepted 19 November 2014 Available online xxx

DJ-1 is a cancer- and Parkinson’s disease-associated protein that participates in different intracellular signaling pathways to protect cells from toxic stresses. DJ-1 expression, oxidation, localization, and phosphorylation are often altered in human tumors, and DJ-1 has been implicated in various aspects of transformation, including uncontrolled proliferation, invasion, metastasis, and resistance to chemotherapy and apoptosis. Despite the strong relationship between DJ-1 and cancer, which made it a particularly attractive therapeutic target for cancer treatment, the detailed mechanisms of how this oncogene coordinates altered signaling with cell survival remains elusive. In this commentary, we discuss the role of DJ-1 in transformation, highlight some of the significant aspects of and prospects for therapeutically targeting the DJ-1 signaling in cancer, and describe what the future may hold. ß 2014 Elsevier Inc. All rights reserved.

Keywords: DJ-1 Cancer Therapeutics Post-translational modification

1. Introduction The human DJ-1 (RS/PARK7/CAP1) gene is located on the distal part of the short arm of chromosome 1 (1p36.12–1p36.33), where many chromosome aberrations in cancers have been reported (see Fig. 1 for details) [1]. The 20 kDa DJ-1 protein, whose sequence is conserved among prokaryotic and eukaryotic cells [2], is ubiquitously expressed in over 22 human tissues. DJ-1 is capable of transforming NIH-3T3 cells when expressed either alone or, to a greater extent, with other oncogenes such as c-Myc or H-Ras, suggesting its pro-oncogenic potential [3]. X-ray crystallographic examination of DJ-1 structure indicates that it exists as a dimer [4], containing domains found in heat shock protein chaperones [5] and ThiJ/PfpI proteases [4,5]. However, the Leu166Pro (L166P) mutation which is linked with autosomal-recessive early-onset Parkinson’s disease (PD) [6] destabilizes the dimer interface and promotes DJ-1 degradation through the ubiquitinproteasome system, resulting in a low level of the protein [7]. DJ-1 is currently recognized as a multifunctional protein with roles such as regulatory subunit of RNA-binding protein [2], redox-regulated chaperone [8], cysteine protease [9], and transcriptional coactivator [10]. Therefore, DJ-1 has been implicated in various aspects of biological processes, including

* Corresponding author at: Room 113, College of Pharmaceutical Sciences, Zijin’gang Campus, Zhejiang University, Hangzhou 310058, China. Tel.: +86 571 88208400; fax: +86 571 88208400. E-mail address: [email protected] (B. Yang). 1 These authors contributed equally to this work.

transcriptional regulation [11], antioxidant stress function [12–14], mitochondrial regulation [15], fertilization [16], and tumor TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis [17]. Despite the relationship between DJ-1 and cancer [18,19], the exact function of DJ-1 in cancer is yet obscure. In this commentary, we discuss the role of DJ-1 in transformation and describe mechanism-based approaches to therapeutically target oncogenic DJ-1 signaling in cancer.

2. DJ-1 is oncogenic in human tumors 2.1. DJ-1 is overexpressed and secreted in human tumors DJ-1 is frequently overexpressed in the majority of tumor types examined (Table 1). Accumulating evidence has shown that DJ-1 is overexpressed in prostate cancer [17], renal carcinoma [20], hepatocellular carcinoma [21], ovarian carcinoma [22], uveal melanoma [23], non-small cell lung carcinoma (NSCLC) [24], breast cancer [25], acute leukemia [26], cervical cancer [27], papillary thyroid cancer [28], pancreatic ductal adenocarcinoma (PDAC) [29], laryngeal squamous cell carcinoma [30], and esophageal squamous cell carcinoma (ESCC) [31]. Interestingly, primary human malignant NSCLC and ESCC tumor samples showed DJ-1 overexpression at both mRNA and protein levels compared with normal adjacent control tissue [24,31], indicating that DJ-1 overexpression is largely restricted to tumor cells and increases with cell transformation. In addition, this study has identified DJ-1 as a potential tumor antigen found in the circulation of breast cancer-bearing patients [25], and the level of DJ-1 in pancreatic juice is higher in pancreatic

http://dx.doi.org/10.1016/j.bcp.2014.11.012 0006-2952/ß 2014 Elsevier Inc. All rights reserved.

Please cite this article in press as: Cao J, et al. DJ-1 as a human oncogene and potential therapeutic target. Biochem Pharmacol (2014), http://dx.doi.org/10.1016/j.bcp.2014.11.012

G Model

BCP-12143; No. of Pages 10 J. Cao et al. / Biochemical Pharmacology xxx (2014) xxx–xxx

2

Fig. 1. Genomic information of human DJ-1 gene. The genomic locus of DJ-1 gene is located on the short arm p36 of chromosome 1 with 23,629 base pairs in length. It is downstream of TNFRSF9 gene (tumor necrosis factor receptor superfamily, member 9) and upstream of ERRFI1 (ERBB receptor feedback inhibitor 1) and RPL7AP18 (ribosomal protein L7a pseudogene 18). DJ-1 contains 7 exons (green boxes), which may be transcribed with two transcript variants. The full-length transcript (NM_007262.4) and encoded protein structure is illustrated. DJ-1 protein is comprised of two core structure regions (yellow color) [5] and a dimerization region (green color) [4]. There are two mutation sites at the relative C-terminus of the protein: 106 and 166 amino acids, respectively.

Table 1 Overview of overexpression of DJ-1 in human tumors and cancer cell lines investigated. Tumor type human

DJ-1

Technique used

Clinical impact

Ref.

Renal carcinoma Hepatocellular carcinoma

Twofold Higher

RT–PCR PCR and western blot

[20] [21]

Ovarian carcinoma Non-small cell lung carcinoma (NSCLC)

RT–PCR RT–PCR and western blot Immunohistochemistry RT–PCR Western blot Immunohistochemistry

Acute leukemia

34/42 6/7 33/67 19/23 11/30 (serum) Lower DJ-1 in 39/49 of pathological complete remission (pCR) cases 8.3-fold (nipple fluid) Higher

None Preoperative AFP, liver cirrhosis, vein invasion, differentiation, and overall survival Overall survival Cell survival Cisplatin resistance and poor prognosis Relapse incidence Circulating antigen Predictor of pCR after neoadjuvant chemotherapy

[33] [26]

Papillary thyroid cancer

2.1-fold

Pancreatic ductal adenocarcinoma (PDAC) Pancreatic cancer

37/51 50/76 2.9-fold (serum)

Two-dimensional electrophoresis and peptide mass fingerprinting Immunohistochemistry Microarray and immunohistochemistry ELISA

Diagnostic biomarker Leukemogenesis and/or disease progression Diagnostic biomarker

[29] [18] [35]

Laryngeal squamous cell carcinoma

59/82

Immunohistochemistry

Esophageal squamous cell carcinoma (ESCC) Glottic squamous cell carcinoma Prostate cancer Uveal melanoma Non-small cell lung carcinoma (NSCLC) Acute leukemia

Higher 51/60 8–13-fold Higher Higher Higher

Immunohistochemistry Immunohistochemistry and western blot Western Blot Western Blot Western Blot RT–PCR

Tumor differentiation Tumor invasion and poor prognosis Tumor differentiation and overall survival Tumor stage, cell differentiation, overall survival Overall survival Overall survival Resistance to cytotoxic agents

Pancreatic ductal adenocarcinoma (PDAC) Pancreatic cancer

Higher

Western Blot RT–PCR and western Blot

Breast cancer

ELISA RT–PCR

Cisplatin resistance Proliferation, cell tolerance to serum starvation Cell migration and invasion Chemoresistance

[22] [24] [34] [39] [25] [32]

[28]

[30] [31] [40] [17] [23] [34] [26] [18] [35]

‘x fold’ or ‘higher’ means authors of the articles did not present a specific value of the elevated DJ-1 levels. Serum or nipple fluid indicates the level of DJ-1 secreted into serum or nipple fluid.

Please cite this article in press as: Cao J, et al. DJ-1 as a human oncogene and potential therapeutic target. Biochem Pharmacol (2014), http://dx.doi.org/10.1016/j.bcp.2014.11.012

G Model

BCP-12143; No. of Pages 10 J. Cao et al. / Biochemical Pharmacology xxx (2014) xxx–xxx

cancer patients than healthy controls [29], which raise the intriguing possibility of extracellular secretion of DJ-1. Interestingly, despite the up-regulation of mRNA levels [32], approximately half of breast cancer cases exhibited low expression of DJ-1 protein, whereas serum [25] and nipple fluid [33] obtained from a large fraction of newly diagnosed breast cancer patients had a high concentration of DJ-1. Therefore, DJ-1 secretion by cancer cells may explain the difference between levels of DJ-1 transcription and protein expression and suggests the measurement of DJ-1 in peripheral blood as a useful marker of detection of the occurrence and development of pancreatic and breast cancer. Taken together, these findings indicate that DJ-1 overexpression and secretion is a frequent event in cancer cells and further emphasizes its potential as a biomarker for cancer diagnosis and prognosis. 2.2. DJ-1 is required for the cancer cell phenotype DJ-1 is required for maintenance of the transformed phenotype of cancer cells, regulating transformed growth, survival, and chemoresistance of several tumor types including prostate cancer [17], NSCLC [34], pancreatic cancer [35], breast cancer [36], leukemia [26], and cervix adenocarcinoma [37]. Knockdown of DJ-1 by small interfering RNA (siRNA) leads to an impaired ability of cell growth and enhanced sensitivity of tumor cells to chemotherapeutic drugs such as TRAIL [17], gemcitabine [35], 20 -benzoyloxycinnamaldehyde [36], dihydroartemisinin [37], etoposide [26], taxol, and cisplatin [34]. Our laboratory has also confirmed that the depletion of DJ-1 increases the sensitivity of tumor cells to cancer chemopreventive and therapeutic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) both in vitro and in vivo [38]. In addition, DJ-1 correlates with tumor metastasis and differentiation of ESCC [31], PDAC [18], and pancreatic cancer [35], whereas knockdown of DJ-1 expression in PDAC cell lines reduces cell migration and invasion potential in vitro and inhibited metastasis in vivo [18]. These findings demonstrate that DJ-1 is functionally required for the transformed behavior of cancer cells and indicate roles for DJ-1 in tumor initiation, progression, and metastatic behavior. 2.3. DJ-1 expression predicts survival and is associated with tumor aggressiveness Reflecting its functional role in cellular transformation, DJ-1 expression profiling may be of prognostic value to predict survival in patients with various tumors types. Elevated DJ-1 expression is associated with tumor progression and decreased survival in patients with pancreatic cancer [18], cervical cancer [27], ESCC [31], NSCLC [39], and glottic squamous cell carcinoma [40]. In other cancer types such as uveal melanoma, DJ-1 expression is greater in later stage tumors, suggesting a role for DJ-1 in tumor aggressiveness and progression [23]. Furthermore, DJ-1 is related to tumor recurrence. The 3-year recurrence of patients with lung cancer expressing high levels of DJ-1 mRNA was higher than that of disease-matched patients with a low level of DJ-1 mRNA [24,39]. Low DJ-1 protein expression is also suggested as a predictor of pathological complete remission (pCR) after neoadjuvant chemotherapy in breast cancer patients [32]. Thus, DJ-1 expression may be useful for identifying patients that are more likely to relapse and those who may benefit from more aggressive adjuvant chemotherapeutic treatment. 3. Oncogenic DJ-1 signaling 3.1. Upstream activators of DJ-1 3.1.1. DJ-1 and oxidative stress DJ-1 participates in a number of apoptotic and cellular defense pathways that are key in determining drug sensitivity. Several

3

studies indicate that hyperactivity of DJ-1 increases the resistance of cancer cells to chemotherapy-induced apoptosis and involved in cellular defense against reactive oxygen species (ROS) [24,41,42]. DJ-1 acts as a redox-sensitive chaperone and as a sensor for oxidative stress [8]; its overexpression protects several kinds of cells such as leukemic [26], neuronal [42], pancreatic [43], and lung carcinoma [24] against various oxidative agents, including UV irradiation, H2O2, anti-cancer drugs, etc. Deletion of this gene sensitizes cell death caused by oxidative and endoplasmic reticulum stresses as well as proteasome inhibitors [13,34,35,41,42,44]. Although the antioxidative activity of DJ-1 has been well established, detailed mechanism of its cytoprotective function remains largely unknown. Some reports suggest that under oxidative stress, DJ-1 translocalizes from cytoplasm to mitochondria, where the protein is oxidized, which provides DJ-1 with stronger cytoprotection activity and reduces oxidative stress [13,45]. In addition, DJ-1 increases glutathione synthesis by upregulating the transcription of glutamate cysteine ligase, a ratelimiting enzyme in glutathione synthesis during oxidative stress [46], while stabilizes the antioxidant transcriptional master regulator Nrf2, which induces the expression of antioxidant genes [12]. Thus, activation of DJ-1 is an important downstream mediator of chemotherapy-induced oxidative stress, which is beneficial to maintaining the intactness of the mitochondria in physiological conditions and survival of tumor cells. 3.2. Effectors of DJ-1 signaling 3.2.1. PTEN The PI3K/Akt pathway is one of the most frequently dysregulated signaling pathways in cancer and an important target for drug development. PI3K signaling plays a fundamental role in tumorigenesis, governing cell proliferation, survival, motility, and angiogenesis [47]. A previous report demonstrated that DJ-1 promotes cell survival in some tumor cells through modulating the PI3K survival pathway by negatively regulating the function of the tumor suppressor gene phosphatase and tensin homolog (PTEN). In mammalian COS-7 cells, primary breast and lung cancer samples, and laryngeal squamous carcinoma cells, DJ1 suppresses PTEN function, thereby profoundly hyperphosphorylates PKB/Akt, a downstream target of PTEN, to increase cell survival [39,48]. Low expression of DJ-1 protein increases PTEN expression, which induces apoptosis by decreasing Akt activation [49]. Therefore, DJ-1 functions in the PI3K survival pathway as a key negative regulator of PTEN that promotes cell proliferation and transformation. 3.2.2. MAPK pathway Given the crucial role that mitogen-activated protein kinase (MAPK) pathway plays in transducing signals from the cell membrane to the nucleus and controlling a wide spectrum of cellular processes, it is perhaps not surprising that several components of the pathway, particularly apoptosis signal-regulating kinase 1 (ASK1), c-jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK) have been directly implicated in oncogenesis. ASK1 is a stress-responsive MAP kinase kinase kinase (MAP3K) regulated by the death protein Daxx. Daxx interacts with ASK1, and by relieving an inhibitory intramolecular interaction between the N- and C-termini of ASK1, allows it to oligomerize and become activated, which in turn activates both JNK and p38 signaling and subsequently promotes cell death [50]. In an attempt to elucidate the mechanism of DJ-1’s cell-preserving function, a yeast twohybrid screen was conducted to reveal that Daxx is a DJ-1interacting partner. In mammalian cells, DJ-1 sequesters Daxx in

Please cite this article in press as: Cao J, et al. DJ-1 as a human oncogene and potential therapeutic target. Biochem Pharmacol (2014), http://dx.doi.org/10.1016/j.bcp.2014.11.012

G Model

BCP-12143; No. of Pages 10 4

J. Cao et al. / Biochemical Pharmacology xxx (2014) xxx–xxx

the nucleus, prevents it from gaining access to the cytoplasm, from binding to and activating its effector ASK1 and therefore, from triggering the ensuing death pathway [51]. All these steps are impaired by the L166P or Cys106Ala (C106A) mutant isoform of DJ-1 [51,52]. These findings suggest that the regulated sequestration of Daxx in the nucleus and keeping ASK1 activation in check is a critical mechanism by which DJ-1 exerts its cytoprotective function. However, under UV irradiation, DJ-1 protects against UVinduced cell death through mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase kinase 1 (MEKK1)SEK1-JNK1 signaling cascade. DJ-1 physically binds to MEKK1 and sequesters MEKK1 within the cytoplasm, thus blocking the UVinduced translocation of MEKK1 into the nucleus and suppressing the downstream activation of SEK1 and JNK1. The L166P mutant of DJ-1 leads to impaired physical association with MEKK1 and facilitates its translocation toward the nucleus, while both L166P mutant and DJ-1 knockdown by siRNA render the cells highly susceptible to the UV-induced activation of the MEKK1-SEK1-JNK1 signaling pathway and cell death [44]. In addition to regulating cell survival, DJ-1 is associated with cancer cell migration and invasion via activating ERK/SRC phosphorylation cascade. Knockdown of DJ-1 expression resulted in decreased ERK1/2 and SRC phosphorylation and reduction of invasion and cell migration potential in pancreatic cancer cells [18]. This finding is in line with other report that shows the importance of ERK1/2 pathway during pancreatic cancer metastasis [53]. Indeed, DJ-1 was first observed to interact with the RASpathway during the transformation of NIH-3T3 cells [3]. Taken together, these findings show that DJ-1 performs a function in the prevention of cell death and promotion of invasion/migration by negative or positive regulation of the MAPK pathway. 3.2.3. p53 p53 is a tumor suppressor whose mutations are found in over 50% of human tumors. In response to various intrinsic and extrinsic stress signals including DNA damage, metabolic changes, hypoxia, and oncogenic activation, p53 initiates cell-cycle arrest, senescence, and apoptosis via negatively regulating the IGF-1/AKT pathway by inducing the expression of p53-target genes such as IGF-BP3 or PTEN, which shut down IGF-1/AKT pathway or decrease activation of AKT, respectively [54]. Several studies have demonstrated an existing link between p53 and DJ-1 [55,56], some of them pointing to an anti-apoptotic function of DJ-1 through repression of p53 transcriptional activity. DJ-1 binds to the C-termini of p53 in a manner dependent on the oxidation of C106 residue [55], thereby interferes with the binding of p53 to promoter DNA to repress the transcription of the proapoptotic factor Bcl-2 associated X (Bax) and inhibits downstream caspase activation. Knockdown of DJ-1 increases Bax protein levels and accelerates caspase-3 activation and cell death induced by UV exposure, suggesting the cytoprotection of DJ-1 is mediated by inhibiting p53-Bax-caspase pathway [11]. This finding is in consistence with a study in zebrafish, which shows that morpholino knockdown of DJ-1 promotes transcription of p53 and expression of Bax, thus leading to increased neuronal cell death in response to H2O2 [57]. This repressive activity on p53 is dependent on the sumoylation of DJ-1, as DJ-1 (K130R), the nonsumoylatable mutant form of DJ-1, shifts from nucleus to cytoplasm, fails to repress p53 transcriptional activity and loses its protective function against UV-induced cell death [56]. However, others have suggested a direct binding of DJ-1 to p53 which restores p53 transcriptional activity by inhibiting sumoylation of p53 through the interaction of DJ-1 with Topors/p53BP3, a ring finger protein binding to both topoisomerase I and p53 as well as a SUMO-1 ligase for p53, thus suggesting a positive regulation of p53 through Topors-mediated sumoylation [58]. Therefore, despite the

controversy of DJ-1-mediated p53 transcriptional activity, downregulation of DJ-1 expression increases p53-mediated apoptosis in both neuroblastoma [11] and a myelodysplastic syndrome model [59], which is associated with decreased overall mortality, thus suggesting the conjunction of DJ-1 expression with p53 may have a central role in determining cell fate by regulating apoptosis. Interestingly, contradictory to the above findings that propose the regulation of p53 by DJ-1, a study using transformed mouse embryonic fibroblasts (MEFs) derived from p53+/+ or p53/ mice showed that p53 prevents the accumulation of DJ-1 protein by a post-transcriptional mechanism, whereas loss of p53 leads to stabilization and enhancement of DJ-1 expression. The increased DJ-1 protein level is responsible for Akt activation and ROS production in transformed p53-mutated cells [19]. This finding suggests that DJ-1 is a target of p53 during tumorigenesis and has a key role in the p53-regulated Akt pathway and p53-driven oxidative stress response [19]. However, it should be noted that the mutant p53 might transcriptionally regulate specific genes not activated by wild-type p53. Thus, it is interesting to know whether DJ-1 is the specific downstream for mutant p53 in future research. One possible mechanism of DJ-1 repression by p53 is through the induction of transcription-independent phosphorylation of DJ-1. As JNK1 is upregulated by p53 [60], and phosphorylation of DJ-1 is inhibited in JNK1 knockdown cells, JNK1 or a downstream target of JNK1 may be involved in p53-dependent phosphorylation inactivation of DJ-1, which facilitates apoptosis [61]. The conflicting signals transduced by DJ-1 and p53 are possibly integrated via negative feedback between the two pathways, which is also found in the crosstalk between Akt and p53. With respect to p53dependent activation of PTEN, increased PTEN levels diminish the function of PIP3 in the activation of PDK-1 and mTORC2, which in turns inhibits the activity of Akt, leading to decreased cell proliferation. On the other hand, activation of Akt in the presence of growth factors leads to the Akt-dependent activation of MDM2, which in turns degrades and inactivates p53, creating a feedback loop in the p53-Akt pathway [62]. Overall, these reports confirm the strong interconnection between p53 and DJ-1 and suggest the existence of a finely regulated loop between the two proteins during tumorigenesis and apoptosis. 3.2.4. HIF-1 A tumor’s ability to adapt to hypoxia is absolutely critical for its survival and progression, and this adaptation is largely mediated by the transcription factor hypoxia-inducible factor-1 (HIF-1) consisting of two subunits-HIF-1a and HIF-1b, of which HIF-1b is expressed constitutively, whereas HIF-1a is highly regulated in response to hypoxia [63]. The stabilization of HIF-1 subunits during hypoxia is at least partly dependent on the stimulation of PI3K/Akt/mTOR pathway, which up-regulates HIF-1 expression at the level of translation and confers protection against apoptosis [64]. As overexpression of DJ-1 positively regulates Akt activity [39], the loss of DJ-1 decreases the expression level of HIF-1a in neuroblastoma cells [65], and the transcription of a variety of HIF1-responsive genes during hypoxia in human osteosarcoma cells and transformed mouse fibroblasts [66]. Under hypoxia, the expression of DJ-1 prevents caspase 3 cleavage and allows a cell to resist apoptosis [66]. Therefore, DJ-1 appears to protect cells against hypoxia-induced cell death partly by stabilizing HIF-1a via Akt activation and is required for their adaptation to severe hypoxic stress. Besides the regulation of PI3K/Akt/mTOR pathway, it remains possible that the ability of DJ-1 to modulate HIF-1 activity also relies on its capacity to interact with other factors such as Von Hippel Lindau (VHL), a tumor-suppressor that is involved in the ubiquitination and degradation of HIF-1a under normoxia or generation of oxidative species [67]. DJ-1 negatively regulates VHL

Please cite this article in press as: Cao J, et al. DJ-1 as a human oncogene and potential therapeutic target. Biochem Pharmacol (2014), http://dx.doi.org/10.1016/j.bcp.2014.11.012

G Model

BCP-12143; No. of Pages 10 J. Cao et al. / Biochemical Pharmacology xxx (2014) xxx–xxx

ubiquitination activity of the HIF-1a by inhibiting HIF-VHL interaction, whereas the loss of DJ-1 leads to lowered HIF-1a levels in models of both hypoxia and oxidative stress, two stresses known to stabilize HIF-1a [68]. Interestingly, contradictory to the above findings that suggest DJ-1 is a downstream responder of hypoxic conditions, a recent report reveals that in the normoxia conditions, the inducible loss of DJ-1 in neuroblatoma cells triggers the generation of a hypoxic state and the accumulation of free radical species that stabilize the HIF-1a [69]. Therefore, future experiments are needed to determine whether the absence of DJ-1 exerts different effects in normoxia and hypoxia or if cell typespecific responses take place. Taken together, these results indicate that DJ-1 stabilizes HIF-1a and increases its transcriptional activity, thereby maintaining cancer cell survival and increasing cell resistance to hypoxic stress. 3.2.5. NQO1 and Nrf2 Cellular metabolism and environmental exposures result in the accumulation of oxidative species and the occurrence of oxidative stress. These oxidative species are detoxified by a gambit of antioxidant enzymes and molecules, and the balance between oxidative species generation and removal determines the oxidative stress on a given tissue [70]. As DJ-1 has been shown to play a role in the oxidative stress response [41] and protection against ROSinduced cell death [51], it is found that loss of DJ-1 leads to deficits in NQO1 (NAD(P)H quinone oxidoreductase 1) [12], a detoxification enzyme shown to increase the efficacy of Mitomycin C (MMC) in vivo [71]. This deficit is attributed to a loss of nuclear factor erythroid 2-related factor (Nrf2), a master regulator of antioxidant transcriptional responses. DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1, and Nrf2’s subsequent ubiquitination. The stabilization of Nrf2 thus protects dopaminergic neurons and cancer cells against oxidative stress [12]. The link between DJ-1 and Nrf2 also exists in DJ-1-KO MEFs, the human lung epithelial cell line Baes2B and mouse lung in vivo [72], but not in brain or primary cortical neuronal and astrocyte cultures [73], which strongly suggest that the regulatory effects as well as the direct interaction between DJ-1 and Nrf2 remain elusive and are cell-type-specific. Therefore, in cancer cells with enhanced expression of DJ-1 and detoxification enzymes, which likely provided a survival advantage, DJ-1 could function as a potential biomarker to define specific antitumor therapies targeting these enzymes. 3.2.6. DISC TRAIL, a member of the TNF ligand superfamily, can induce apoptosis in a variety of tumor cells through its receptors, death receptor 4 (DR4) and DR5 [74]. Knockdown of DJ-1 sensitizes prostatic cancer PC-3 cell line and thyroid carcinoma cells to TRAIL-induced apoptosis, whereas overexpression of DJ-1 protects cells from TRAIL-induced apoptosis [17,75]. Further studies showed that DJ-1 inhibits TRAIL-induced apoptosis by blocking Fas-associated protein death domain (FADD)-mediated procaspase-8 activation. Wild-type DJ-1, but not the PD-associated mutant L166P, competes with pro-caspase-8 to bind to FADD at the death effector domain, thereby inhibiting the formation of the death-inducing signaling complex (DISC), repressing the recruitment and activation of pro-caspase-8 to the active form of caspase8 [76], and inhibiting the cleavage and activation of the effector caspase-3 or -7 [77]. Thus, these studies suggest that DJ-1 protects against TRAIL-induced apoptosis through the regulation of DISC formation. 3.2.7. Survivin Survivin, a member of the inhibitors-of-apoptosis gene family, is expressed in a cell-cycle-dependent manner in all the most

5

common cancers but not in normal differentiated adult tissues [78]. Survivin expression is regulated by PI3K signal transduction pathway on both mRNA level and protein level [79] and is negatively correlated to PTEN expression in cancers [80]. Under normal circumstances, PTEN inhibits survivin expression through PI3K/Akt pathways. When PTEN activity gets lost, the expression of survivin will increase and then promote cell proliferation and inhibit apoptosis [81]. Since DJ-1 expression correlates negatively with PTEN immunoreactivity and positively with PKB/Akt hyperphosphorylation [39], it is not surprising to find a positive correlation between DJ-1 and survivin gene expression. DJ-1 promotes the carcinogenesis of laryngeal cells by up-regulating the survivin gene expression [30], whereas RNA interference with DJ-1 gene significantly suppressed expression of survivin gene mRNA and protein levels, and therefore inhibits the viability of laryngeal carcinoma Hep-2 cells [82]. In conclusion, these studies demonstrate a link between the DJ-1 gene and survivin gene, and their vital roles in the occurrence and development of laryngeal carcinoma. 3.2.8. Autophagy and apoptosis Autophagy is an evolutionarily conserved pathway to degrade cytoplasmic proteins and organelles via lysosomes so as to have a positive effect on cell health as potentially harmful protein aggregates and damaged organelles can be recycled. However, in response to stress conditions encountered by tumor cells, autophagy may affect cell death decisions either to protect the cell from starvation or dysfunctional mitochondria or aid its demise by degrading essential components of the cytosol. Therefore, predicting the specific circumstances where autophagy may have a pro-survival or a pro-death role is difficult. Nevertheless, the overarching theme from the literature is that autophagy, and autophagy proteins, play a central role in integrating many stress signals to determine the fate of cells [83]. It is found that autophagy level is decreased in prostate cancer, breast cancer, and ovarian carcinoma [84–86], in which DJ-1 is highly expressed [17,24]. As silencing of DJ-1 increases autophagy level in human osteosarcoma cells [66], it is possible that DJ1 represses autophagy to induce tumorigenesis. From yeast to mammals, much of autophagy processes are strictly regulated by conserved autophagy-related (Atg) proteins [87]. Beclin 1, a mammalian homolog of yeast Atg6, is the first identified mammalian Atg protein that induces the formation of autophagosomes and represses tumorigenesis [84,87]. The up-regulation of Beclin 1 is one of the critical factors that induce autophagy [87]. In cancer cell lines, DJ-1 represses Beclin 1 transcription to down-regulate Beclin 1 mRNA and protein levels, while the knockdown of DJ-1 up-regulates the level of Beclin 1 in a p53independent manner [88]. Therefore, the repression of Beclin 1 by DJ-1 may inhibit autophagy, and thereby play a role in tumorigenesis. Further studies indicate that Beclin 1 transcription activation is dependent on the JNK-mediated c-Jun transcriptional activity [89], and the regulation of Beclin 1 by DJ-1 is completely blocked by a JNK inhibitor SP600125, therefore suggesting that DJ-1 regulates Beclin 1 transcription via JNK pathway [88]. Another key indicator of autophagy is the degradation of p62. The elimination of p62 by autophagy is essential to suppress tumor formation, while the impairment of autophagy leads to accumulation of p62 and contributes to tumorigenesis [90]. In contrast with the up-regulated Beclin 1, knockdown of DJ-1 increases p62 degradation via JNK pathway and enhances autophagic cell death [88]. In summary, the upregulation of DJ-1 in cancers may function to inhibit autophagy via suppressing Beclin 1 and accumulating p62, thereby inducing tumorigenesis.

Please cite this article in press as: Cao J, et al. DJ-1 as a human oncogene and potential therapeutic target. Biochem Pharmacol (2014), http://dx.doi.org/10.1016/j.bcp.2014.11.012

G Model

BCP-12143; No. of Pages 10 6

J. Cao et al. / Biochemical Pharmacology xxx (2014) xxx–xxx

Contradictory to the previous studies that suggest the prodeath role of autophagy during tumorigenesis, there are evidence supporting the protective role of autophagy, which tends to inhibit apoptosis in response to chemotherapies [91,92]. One potential stimulus inter-connecting autophagy and apoptosis is ROS, which a modest amount promotes tumor survival while an excessive level paradoxically directs cells toward apoptosis [93]. We found that under mild oxidative stress induced by low concentrations of 4-HPR, moderate oxidation of DJ-1 is recruited to inhibit the activity of ASK1 and maintain cell viability by activating autophagy; under a lethal level of oxidative stress, excessive oxidized DJ-1 dissociates from ASK1 and activates it, thereby initiating p38 activation and enabling the cells to commit to apoptosis. Therefore, our results reveal that the different oxidation states

of DJ-1 function as a cellular redox sensor of ROS caused by 4HPR chemotherapy and determine the cancer cell fate of autophagy or apoptosis [38]. In conclusion, DJ-1 partially affects the cell death decisions via modulating autophagy and determines the progression and treatment of cancer. 4. Therapeutic targeting of DJ-1 As described above (Fig. 2), there is compelling evidence for DJ1 as a target for intervention in cancer. In principle, interventions in DJ-1 could be afforded by: (i) modulating transcription/ translation, for instance, through an anti-sense approach; (ii) blocking formation of homodimer; and (iii) interfering protein function. We will comment here on those avenues where progresses can be made in DJ-1 intervention.

Fig. 2. Schematic representation of DJ-1 oncogenic mechanisms of action. In DJ-1-mediated tumorigenesis and proliferation, stimulated DJ-1 results in the activation of downstream pathways, including the PI3K/Akt pathway, the MAPK pathway, and the p53/Bax pathway. As a result, tumorigenic processes, such as cellular proliferation, survival, self-renewal, migration, and invasion, are supported. P: phosphorylation; S: sumoylation; Ub: ubiquitination; p53 BS: p53 binding site.

Please cite this article in press as: Cao J, et al. DJ-1 as a human oncogene and potential therapeutic target. Biochem Pharmacol (2014), http://dx.doi.org/10.1016/j.bcp.2014.11.012

G Model

BCP-12143; No. of Pages 10 J. Cao et al. / Biochemical Pharmacology xxx (2014) xxx–xxx

7

Table 2 RNA interference targeted at DJ-1. Effects

Tumor type

Ref.

Sensitized cells to anti-tumor agent-induced apoptosis

Prostate cancer Leukemia Pancreatic cancer Breast cancer Thyroid carcinoma Leukemia Laryngeal squamous cell carcinoma Mouse neuroblastoma PDAC Prostate cancer, ovarian carcinoma, breast cancer, and lung carcinoma

[17] [26] [35] [36] [75] [26] [40,82] [42] [18] [88]

Suppressed cell viability and enhanced apoptosis Enhanced cell death induced by oxidative stress, ER stress, and proteasome inhibition Reduced cell migration and invasion potential in vitro and inhibited metastasis in vivo Induced pro-death autophagy

4.1. RNA interference Through a mechanism known as RNA interference (RNAi), siRNA or its precursor known as short-hairpin RNA (shRNA) molecules can target complementary mRNA strands for degradation, thus specifically inhibiting gene expression. Since the discovery of RNAi, several early-phase trials of RNAi therapies have reported clinical responses in cancer patients [94]. As DJ-1 is a promising target for cancer therapy, while its down-regulation can serve as a potent measurement of the efficiency of chemotherapeutic and chemosensitizing agents, the design of an RNAi-based drug targeting DJ-1 can be a viable therapeutic strategy. Some preclinical studies using RNA interference targeted at DJ-1 have shown inhibition against tumor initiation, progression, and metastatic behavior (Table 2). However, despite the success in pre-clinical reports, design and improvements in RNAi-based DJ-1 intervention therapeutics are still needed in a variety of areas, such as safety and delivery efficiency of siRNAs into tumors. 4.2. Blockage of dimerization L166P mutation of DJ-1, which is located on a C-terminal helix in the homodimer interface, is shown to be associated with early onset of familial PD [95]. Compared to wild-type DJ-1 which forms a homodimer, this mutant loses its ability to dimerize [96], which results in structural instability, rapid degradation by the ubiquitinproteasome system [7], and loss of antioxidative function [41]. One ligand-binding hot spot for DJ-1 has been identified in this dimer interface, where a pharmacological chaperone can bind to and increase or decrease the stability of the dimeric structure [97]. Hence, interfering with the homodimer formation and stabilization of DJ-1 may serve to confront the overexpression of DJ-1 in tumor tissues.

silico virtual screening of 30,000 chemical compounds in the University Compound Project (UCP) identified a DJ-1 modulator, 2[3-(benzyloxy)-4-methoxyphenyl]-N-[2-(7-methoxy-1,3-benzodioxol-5-yl)ethyl]acetamide (UCP0054278), which has the highest binding constant toward the pocket of the SO2H-oxidized C106 region. UCP0054278 significantly inhibited H2O2-induced cell death and the production of ROS in normal neuroblastoma SHSY5Y cells, but not in DJ-1-knockdown cells [100]. These results suggest that UCP0054278 interacts with endogenous DJ-1 and then exhibits antioxidant and neuroprotective responses, which provide compelling evidence that the development of small molecular compounds targeting the cytoprotective function of DJ-1 is an alternative way of effectively improving the outcome of chemotherapies. 5. Conclusions Our current knowledge demonstrates that DJ-1 is oncogenic in a variety of human cancers. Functionally, DJ-1 is required for multiple aspects of the transformed phenotype and appears to participate in the initiation, progression, and metastatic stages of cancer. The negative regulation of tumor suppression genes and the careful modulation of autophagy and apoptosis all contribute to the cytoprotective function of DJ-1 and tumorigenesis. In addition, DJ-1 has been shown to promote chemoresistance in a number of cancer types and knockdown of DJ-1 sensitizes these tumor cells to chemotherapeutics. These facets alone are sufficient to encourage further studies on DJ-1 inhibitors and their applications in research and therapy. Unfortunately, the current situation shows a deficiency of adequate studies focusing on both structural and functional analysis of DJ-1 that hopefully will be filled in the next years. 6. Future directions

4.3. Interference with protein function Both the crystal structure of DJ-1 and a substantial number of experiments have indicated that C106 might be an important residue for the function of DJ-1 [38,98], with multi-oxidized forms of C106 observed (such as –SO2 and –SO3) [98]. Oxidation of C106 is essential for DJ-1 localization to the mitochondria [99], binding affinity to p53, and repression of p53-dependent gene transcription [55], all of which demonstrated cell-protective effect. The C106S mutant of DJ-1, which is a substitution mutant from cysteine to serine, possesses little or no protective activity against neuronal cell death induced by oxidative stress [13,14]. Considering the clinical limitations of RNA interference and the discovery of a ligand-binding hot spot for DJ-1 in the region containing C106 [97], the design of small molecular compounds that selectively bind to DJ-1 to prevent oxidization at its C106 residue may be an effective strategy for inactivating DJ-1. An in

From the data commented here, it clearly appears that DJ-1 has been an ideal target for biochemical studies that shed light on how it is oxidized and activated by oxidative stress and how these events work in concert with downstream effectors such as p53 and HIF-1a. As discussed above, several feasible approaches have been proposed to modulate oncogenic DJ-1 function for cancer therapeutics. However, to therapeutically benefit from DJ-1 targeting in human cancers, barriers must still be breached. Given the astonishing range of candidate interactors that DJ-1 has been proposed to bind directly to in the aforementioned studies, the question arises whether DJ-1 binds to different proteins in diverse cellular contexts and experimental paradigms. Sightings of DJ-1 have been reported in cellular compartments as diverse as cytoplasm, mitochondria, and nucleus, which may be indicative of the diverse roles DJ-1 played in various subcellular environments [2,7,13]. Therefore, more studies should be focused

Please cite this article in press as: Cao J, et al. DJ-1 as a human oncogene and potential therapeutic target. Biochem Pharmacol (2014), http://dx.doi.org/10.1016/j.bcp.2014.11.012

G Model

BCP-12143; No. of Pages 10 J. Cao et al. / Biochemical Pharmacology xxx (2014) xxx–xxx

8

on (i) addressing whether this protein exists as a part of a larger protein complex, (ii) elucidating the relative influence of the cellular context (tissue versus cell-based) on its interactome, (iii) exploring whether acute exposure to oxidative stressors alters the molecular environment of DJ-1, and (iv) identifying the underlying mechanisms behind DJ-1’s role in chemoresistance, in conjunction with using distinct targets of DJ-1 signaling that can be developed as robust and sensitive biomarkers, may lead to more successful clinical trials with a higher probability of attaining better patient outcomes. In conclusion, much remains to be learned about how DJ-1 is flexibly integrated to maximize tumor growth, and addressing these questions might help to facilitate the development of novel strategies (siRNA, small molecules) or therapeutic combinations to target DJ-1 in human cancers. Acknowledgments We apologize to our peer researchers whose work could not be cited because of reference limits. We thank all members of our laboratory who critically commented on this manuscript and have contributed to the investigation of DJ-1. This work was funded by National Natural Science Foundation of China (Nos. 81402951 and 81202558) and China Postdoctoral Science Foundation (No. 2014M550330). References [1] Taira T, Takahashi K, Kitagawa R, Iguchi-Ariga SMM, Ariga H. Molecular cloning of human and mouse DJ-1 genes and identification of Sp1-dependent activation of the human DJ-1 promoter. Gene 2001;263:285–92. [2] Hod Y, Pentyala SN, Whyard TC, El-Maghrabi MR. Identification and characterization of a novel protein that regulates RNA-protein interaction. Journal of Cellular Biochemistry 1999;72:435–44. [3] Nagakubo D, Taira T, Kitaura H, Ikeda M, Tamai K, Iguchi-Ariga SM, et al. DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochemical and Biophysical Research Communications 1997;231:509–13. [4] Tao X, Tong L. Crystal structure of human DJ-1, a protein associated with early onset Parkinson’s disease. The Journal of Biological Chemistry 2003;278: 31372–79. [5] Lee SJ, Kim SJ, Kim IK, Ko J, Jeong CS, Kim GH, et al. Crystal structures of human DJ-1 and Escherichia coli Hsp31, which share an evolutionarily conserved domain. The Journal of Biological Chemistry 2003;278:44552–59. [6] Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003;299:256–9. [7] Miller DW, Ahmad R, Hague S, Baptista MJ, Canet-Aviles R, McLendon C, et al. L166P mutant DJ-1, causative for recessive Parkinson’s disease, is degraded through the ubiquitin-proteasome system. The Journal of Biological Chemistry 2003;278:36588–95. [8] Shendelman S, Jonason A, Martinat C, Leete T, Abeliovich A. DJ-1 is a redoxdependent molecular chaperone that inhibits alpha-synuclein aggregate formation. PLoS Biology 2004;2:e362. [9] Olzmann JA, Brown K, Wilkinson KD, Rees HD, Huai Q, Ke H, et al. Familial Parkinson’s disease-associated L166P mutation disrupts DJ-1 protein folding and function. The Journal of Biological Chemistry 2004;279:8506–15. [10] Xu J, Zhong N, Wang H, Elias JE, Kim CY, Woldman I, et al. The Parkinson’s disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis. Human Molecular Genetics 2005;14:1231–41. [11] Fan J, Ren H, Jia N, Fei E, Zhou T, Jiang P, et al. DJ-1 decreases Bax expression through repressing p53 transcriptional activity. The Journal of Biological Chemistry 2008;283:4022–30. [12] Clements CM, McNally RS, Conti BJ, Mak TW, Ting JPDJ-1. A cancer- and Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proceedings of the National Academy of Sciences of the United States of America 2006;103:15091–96. [13] Canet-Aviles RM, Wilson MA, Miller DW, Ahmad R, McLendon C, Bandyopadhyay S, et al. The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proceedings of the National Academy of Sciences of the United States of America 2004;101:9103–8. [14] Takahashi-Niki K, Niki T, Taira T, Iguchi-Ariga SM, Ariga H. Reduced antioxidative stress activities of DJ-1 mutants found in Parkinson’s disease patients. Biochemical and Biophysical Research Communications 2004;320: 389–97. [15] McCoy MK, Cookson MR. DJ-1 regulation of mitochondrial function and autophagy through oxidative stress. Autophagy 2011;7:531–2.

[16] Okada M, Matsumoto K, Niki T, Taira T, Iguchi-Ariga SM, Ariga H. DJ-1, a target protein for an endocrine disrupter, participates in the fertilization in mice. Biological & Pharmaceutical Bulletin 2002;25:853–6. [17] Hod Y. Differential control of apoptosis by DJ-1 in prostate benign and cancer cells. Journal of Cellular Biochemistry 2004;92:1221–33. [18] He X, Zheng Z, Li J, Ben Q, Liu J, Zhang J, et al. DJ-1 promotes invasion and metastasis of pancreatic cancer cells by activating SRC/ERK/uPA. Carcinogenesis 2012;33:555–62. [19] Vasseur S, Afzal S, Tomasini R, Guillaumond F, Tardivel-Lacombe J, Mak TW, et al. Consequences of DJ-1 upregulation following p53 loss and cell transformation. Oncogene 2012;31:664–70. [20] Sitaram RT, Cairney CJ, Grabowski P, Keith WN, Hallberg B, Ljungberg B, et al. The PTEN regulator DJ-1 is associated with hTERT expression in clear cell renal cell carcinoma. International Journal of Cancer 2009;125:783–90. [21] Liu S, Yang Z, Wei H, Shen W, Liu J, Yin Q, et al. Increased DJ-1 and its prognostic significance in hepatocellular carcinoma. Hepato-gastroenterology 2010;57:1247–56. [22] Davidson B, Hadar R, Schlossberg A, Sternlicht T, Slipicevic A, Skrede M, et al. Expression and clinical role of DJ-1, a negative regulator of PTEN, in ovarian carcinoma. Human Pathology 2008;39:87–95. [23] Pardo M, Garcia A, Thomas B, Pineiro A, Akoulitchev A, Dwek RA, et al. The characterization of the invasion phenotype of uveal melanoma tumour cells shows the presence of MUC18 and HMG-1 metastasis markers and leads to the identification of DJ-1 as a potential serum biomarker. International Journal of Cancer 2006;119:1014–22. [24] MacKeigan JP, Clements CM, Lich JD, Pope RM, Hod Y, Ting JP. Proteomic profiling drug-induced apoptosis in non-small cell lung carcinoma: identification of RS/DJ-1 and RhoGDIalpha. Cancer Research 2003;63:6928–34. [25] Le Naour F, Misek DE, Krause MC, Deneux L, Giordano TJ, Scholl S, et al. Proteomics-based identification of RS/DJ-1 as a novel circulating tumor antigen in breast cancer. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2001;7:3328–35. [26] Liu H, Wang M, Li M, Wang D, Rao Q, Wang Y, et al. Expression and role of DJ-1 in leukemia. Biochemical and Biophysical Research Communications 2008;375:477–83. [27] Arnouk H, Merkley MA, Podolsky RH, Stoppler H, Santos C, Alvarez M, et al. Characterization of molecular markers indicative of cervical cancer progression. Proteomics Clinical Applications 2009;3:516–27. [28] Giusti L, Iacconi P, Ciregia F, Giannaccini G, Donatini GL, Basolo F, et al. Fineneedle aspiration of thyroid nodules: proteomic analysis to identify cancer biomarkers. Journal of Proteome Research 2008;7:4079–88. [29] Tian M, Cui YZ, Song GH, Zong MJ, Zhou XY, Chen Y, et al. Proteomic analysis identifies MMP-9, DJ-1 and A1BG as overexpressed proteins in pancreatic juice from pancreatic ductal adenocarcinoma patients. BMC Cancer 2008;8:241. [30] Shen Z, Ren Y, Ye D, Guo J, Kang C, Ding H. Significance and relationship between DJ-1 gene and surviving gene expression in laryngeal carcinoma. European Journal of Histochemistry 2011;55:e9. [31] Yuen HF, Chan YP, Law S, Srivastava G, El-Tanani M, Mak TW, et al. DJ-1 could predict worse prognosis in esophageal squamous cell carcinoma. Cancer Epidemiology Biomarkers & Prevention: A Publication of the American Association for Cancer Research cosponsored by the American Society of Preventive Oncology 2008;17:3593–602. [32] Kawate T, Iwaya K, Kikuchi R, Kaise H, Oda M, Sato E, et al. DJ-1 protein expression as a predictor of pathological complete remission after neoadjuvant chemotherapy in breast cancer patients. Breast Cancer Research and Treatment 2013;139:51–9. [33] Oda M, Makita M, Iwaya K, Akiyama F, Kohno N, Tsuchiya B, et al. High levels of DJ-1 protein in nipple fluid of patients with breast cancer. Cancer Science 2012;103:1172–6. [34] Zeng HZ, Qu YQ, Zhang WJ, Xiu B, Deng AM, Liang AB. Proteomic analysis identified DJ-1 as a cisplatin resistant marker in non-small cell lung cancer. International Journal of Molecular Sciences 2011;12:3489–99. [35] Chen Y, Kang M, Lu W, Guo Q, Zhang B, Xie Q, et al. DJ-1, a novel biomarker and a selected target gene for overcoming chemoresistance in pancreatic cancer. Journal of Cancer Research and Clinical Oncology 2012;138:1463–74. [36] Ismail IA, Kang HS, Lee HJ, Kwon BM, Hong SH. 20 -Benzoyloxycinnamaldehyde-mediated DJ-1 upregulation protects MCF-7 cells from mitochondrial damage. Biological & Pharmaceutical Bulletin 2012;35:895–902. [37] Zhu H, Liao SD, Shi JJ, Chang LL, Tong YG, Cao J, et al. DJ-1 mediates the resistance of cancer cells to dihydroartemisinin through reactive oxygen species removal. Free Radical Biology & Medicine 2014;71C:121–32. [38] Cao J, Ying M, Xie N, Lin G, Dong R, Zhang J, et al. The oxidation states of DJ-1 dictate the cell fate in response to oxidative stress triggered by 4-HPR: autophagy or apoptosis? Antioxidants & Redox Signaling 2014;21:1443–59. [39] Kim RH, Peters M, Jang Y, Shi W, Pintilie M, Fletcher GC, et al. DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 2005;7:263–73. [40] Zhu XL, Wang ZF, Lei WB, Zhuang HW, Jiang HY, Wen WP. DJ-1: a novel independent prognostic marker for survival in glottic squamous cell carcinoma. Cancer Science 2010;101:1320–5. [41] Taira T, Saito Y, Niki T, Iguchi-Ariga SM, Takahashi K, Ariga H. DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Reports 2004;5:213–8. [42] Yokota T, Sugawara K, Ito K, Takahashi R, Ariga H, Mizusawa H. Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition. Biochemical and Biophysical Research Communications 2003;312:1342–8.

Please cite this article in press as: Cao J, et al. DJ-1 as a human oncogene and potential therapeutic target. Biochem Pharmacol (2014), http://dx.doi.org/10.1016/j.bcp.2014.11.012

G Model

BCP-12143; No. of Pages 10 J. Cao et al. / Biochemical Pharmacology xxx (2014) xxx–xxx [43] Inberg A, Linial M. Protection of pancreatic beta-cells from various stress conditions is mediated by DJ-1. The Journal of Biological Chemistry 2010;285:25686–98. [44] Mo JS, Kim MY, Ann EJ, Hong JA, Park HS. DJ-1 modulates UV-induced oxidative stress signaling through the suppression of MEKK1 and cell death. Cell Death and Differentiation 2008;15:1030–41. [45] Junn E, Jang WH, Zhao X, Jeong BS, Mouradian MM. Mitochondrial localization of DJ-1 leads to enhanced neuroprotection. Journal of Neuroscience Research 2009;87:123–9. [46] Zhou W, Freed CR. DJ-1 up-regulates glutathione synthesis during oxidative stress and inhibits A53T alpha-synuclein toxicity. The Journal of Biological Chemistry 2005;280:43150–58. [47] Massacesi C, di Tomaso E, Fretault N, Hirawat S. Challenges in the clinical development of PI3K inhibitors. Annals of the New York Academy of Sciences 2013;1280:19–23. [48] Wang B, Qin H, Wang Y, Chen W, Luo J, Zhu X, et al. Effect of DJ-1 overexpression on the proliferation, apoptosis, invasion and migration of laryngeal squamous cell carcinoma SNU-46 cells through PI3K/AKT/mTOR. Oncology Reports 2014. [49] Kim YC, Kitaura H, Taira T, Iguchi-Ariga SM, Ariga H. Oxidation of DJ-1dependent cell transformation through direct binding of DJ-1 to PTEN. International Journal of Oncology 2009;35:1331–41. [50] Runchel C, Matsuzawa A, Ichijo H. Mitogen-activated protein kinases in mammalian oxidative stress responses. Antioxidants & Redox Signaling 2011;15:205–18. [51] Junn E, Taniguchi H, Jeong BS, Zhao X, Ichijo H, Mouradian MM. Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death. Proceedings of the National Academy of Sciences of the United States of America 2005;102:9691–6. [52] Waak J, Weber SS, Gorner K, Schall C, Ichijo H, Stehle T, et al. Oxidizable residues mediating protein stability and cytoprotective interaction of DJ-1 with apoptosis signal-regulating kinase 1. The Journal of Biological Chemistry 2009;284:14245–57. [53] Tan X, Egami H, Abe M, Nozawa F, Hirota M, Ogawa M. Involvement of MMP-7 in invasion of pancreatic cancer cells through activation of the EGFR mediated MEK-ERK signal transduction pathway. Journal of Clinical Pathology 2005;58:1242–8. [54] Feng Z. p53 regulation of the IGF-1/AKT/mTOR pathways and the endosomal compartment. Cold Spring Harbor Perspectives in Biology 2010;2:a001057. [55] Kato I, Maita H, Takahashi-Niki K, Saito Y, Noguchi N, Iguchi-Ariga SM, et al. Oxidized DJ-1 inhibits p53 by sequestering p53 from promoters in a DNAbinding affinity-dependent manner. Molecular and Cellular Biology 2013;33:340–59. [56] Fan J, Ren H, Fei E, Jia N, Ying Z, Jiang P, et al. Sumoylation is critical for DJ-1 to repress p53 transcriptional activity. FEBS Letters 2008;582:1151–6. [57] Bretaud S, Allen C, Ingham PW, Bandmann O. p53-dependent neuronal cell death in a DJ-1-deficient zebrafish model of Parkinson’s disease. Journal of Neurochemistry 2007;100:1626–35. [58] Shinbo Y, Taira T, Niki T, Iguchi-Ariga SM, Ariga H. DJ-1 restores p53 transcription activity inhibited by Topors/p53BP3. International Journal of Oncology 2005;26:641–8. [59] Marcondes AM, Li X, Gooley TA, Milless B, Deeg HJ. Identification of DJ-1/ PARK-7 as a determinant of stroma-dependent and TNF-alpha-induced apoptosis in MDS using mass spectrometry and phosphopeptide analysis. Blood 2010;115:1993–2002. [60] Rahman-Roblick R, Roblick UJ, Hellman U, Conrotto P, Liu T, Becker S, et al. p53 targets identified by protein expression profiling. Proceedings of the National Academy of Sciences of the United States of America 2007;104:5401–6. [61] Rahman-Roblick R, Hellman U, Becker S, Bader FG, Auer G, Wiman KG, et al. Proteomic identification of p53-dependent protein phosphorylation. Oncogene 2008;27:4854–9. [62] Gottlieb TM, Leal JF, Seger R, Taya Y, Oren M. Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene 2002;21:1299–303. [63] Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006;441:437–43. [64] Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, et al. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Research 2000;60:1541–5. [65] Sheng C, Heng X, Zhang G, Xiong R, Li H, Zhang S, et al. DJ-1 deficiency perturbs microtubule dynamics and impairs striatal neurite outgrowth. Neurobiology of Aging 2013;34:489–98. [66] Vasseur S, Afzal S, Tardivel-Lacombe J, Park DS, Iovanna JL, Mak TW. DJ-1/ PARK7 is an important mediator of hypoxia-induced cellular responses. Proceedings of the National Academy of Sciences of the United States of America 2009;106:1111–6. [67] Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, et al. von Hippel-Lindau disease. Lancet 2003;361:2059–67. [68] Parsanejad M, Zhang Y, Qu D, Irrcher I, Rousseaux MW, Aleyasin H, et al. Regulation of the VHL/HIF-1 pathway by DJ-1. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 2014;34:8043–50. [69] Foti R, Zucchelli S, Biagioli M, Roncaglia P, Vilotti S, Calligaris R, et al. Parkinson disease-associated DJ-1 is required for the expression of the glial

[70]

[71]

[72]

[73] [74] [75]

[76]

[77]

[78] [79] [80] [81]

[82]

[83] [84]

[85]

[86]

[87] [88]

[89]

[90] [91]

[92]

[93]

[94] [95]

[96]

[97]

[98]

9

cell line-derived neurotrophic factor receptor RET in human neuroblastoma cells. Journal of Biological Chemistry 2010;285:18565–74. Limon-Pacheco J, Gonsebatt ME. The role of antioxidants and antioxidantrelated enzymes in protective responses to environmentally induced oxidative stress. Mutation Research 2009;674:137–47. Begleiter A, Leith MK, Thliveris JA, Digby T. Dietary induction of NQO1 increases the antitumour activity of mitomycin C in human colon tumours in vivo. British Journal of Cancer 2004;91:1624–31. Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, Singh A, et al. Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1. American Journal of Respiratory and Critical Care Medicine 2008;178:592–604. Gan L, Johnson DA, Johnson JA. Keap1-Nrf2 activation in the presence and absence of DJ-1. The European Journal of Neuroscience 2010;31:967–77. Johnstone RW, Frew AJ, Smyth MJ. The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nature Reviews Cancer 2008;8:782–98. Zhang HY, Wang HQ, Liu HM, Guan Y, Du ZX. Regulation of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by DJ-1 in thyroid cancer cells. Endocrine-related Cancer 2008;15:535–44. Fu K, Ren H, Wang Y, Fei E, Wang H, Wang G. DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD. Oncogene 2012;31:1311–22. Muzio M, Salvesen GS, Dixit VM. FLICE induced apoptosis in a cell-free system. Cleavage of caspase zymogens. The Journal of Biological Chemistry 1997;272:2952–6. Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nature Medicine 1997;3:917–21. Carter BZ, Milella M, Altieri DC, Andreeff M. Cytokine-regulated expression of survivin in myeloid leukemia. Blood 2001;97:2784–90. Guha M, Altieri DC. Survivin as a global target of intrinsic tumor suppression networks. Cell Cycle 2009;8:2708–10. Suzuki A, Hayashida M, Ito T, Kawano H, Nakano T, Miura M, et al. Survivin initiates cell cycle entry by the competitive interaction with Cdk4/ p16(INK4a) and Cdk2/cyclin E complex activation. Oncogene 2000;19:3225–34. Shen Z, Jiang Z, Ye D, Xiao B, Zhang X, Guo J. Growth inhibitory effects of DJ-1small interfering RNA on laryngeal carcinoma Hep-2 cells. Medical Oncology 2011;28:601–7. Macintosh RL, Ryan KM. Autophagy in tumour cell death. Seminars in Cancer Biology 2013;23:344–51. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999;402:672–6. DiPaola RS, Dvorzhinski D, Thalasila A, Garikapaty V, Doram D, May M, et al. Therapeutic starvation and autophagy in prostate cancer: a new paradigm for targeting metabolism in cancer therapy. The Prostate 2008;68:1743–52. Shen Y, Li DD, Wang LL, Deng R, Zhu XF. Decreased expression of autophagyrelated proteins in malignant epithelial ovarian cancer. Autophagy 2008;4:1067–8. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annual Review of Genetics 2009;43:67–93. Ren H, Fu K, Mu C, Li B, Wang D, Wang G. DJ-1, a cancer and Parkinson’s disease associated protein, regulates autophagy through JNK pathway in cancer cells. Cancer Letters 2010;297:101–8. Li DD, Wang LL, Deng R, Tang J, Shen Y, Guo JF, et al. The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells. Oncogene 2009;28:886–98. Moscat J, Diaz-Meco MT. p62 at the crossroads of autophagy, apoptosis, and cancer. Cell 2009;137:1001–4. Cook KL, Shajahan AN, Warri A, Jin L, Hilakivi-Clarke LA, Clarke R. Glucoseregulated protein 78 controls cross-talk between apoptosis and autophagy to determine antiestrogen responsiveness. Cancer Research 2012;72:3337–49. Lepine S, Allegood JC, Edmonds Y, Milstien S, Spiegel S. Autophagy induced by deficiency of sphingosine-1-phosphate phosphohydrolase 1 is switched to apoptosis by calpain-mediated autophagy-related gene 5 (Atg5) cleavage. Journal of Biological Chemistry 2011;286:44380–90. Gupta SC, Hevia D, Patchva S, Park B, Koh W, Aggarwal BB. Upsides and downsides of reactive oxygen species for cancer: the roles of reactive oxygen species in tumorigenesis, prevention, and therapy. Antioxidants & Redox Signaling 2012;16:1295–322. Wu SY, Lopez-Berestein G, Calin GA, Sood AK. RNAi therapies drugging the undruggable. Science Translational Medicine 2014;6:240ps7. Wilson MA, Collins JL, Hod Y, Ringe D, Petsko GA. The 1.1-A resolution crystal structure of DJ-1, the protein mutated in autosomal recessive early onset Parkinson’s disease. Proceedings of the National Academy of Sciences of the United States of America 2003;100:9256–61. Moore DJ, Zhang L, Dawson TM, Dawson VL. A missense mutation (L166P) in DJ-1, linked to familial Parkinson’s disease, confers reduced protein stability and impairs homo-oligomerization. Journal of Neurochemistry 2003;87: 1558–67. Landon MR, Lieberman RL, Hoang QQ, Ju S, Caaveiro JM, Orwig SD, et al. Detection of ligand binding hot spots on protein surfaces via fragment-based methods: application to DJ-1 and glucocerebrosidase. Journal of ComputerAided Molecular Design 2009;23:491–500. Wilson MA. The role of cysteine oxidation in DJ-1 function and dysfunction. Antioxidants & Redox Signaling 2011;15:111–22.

Please cite this article in press as: Cao J, et al. DJ-1 as a human oncogene and potential therapeutic target. Biochem Pharmacol (2014), http://dx.doi.org/10.1016/j.bcp.2014.11.012

G Model

BCP-12143; No. of Pages 10 10

J. Cao et al. / Biochemical Pharmacology xxx (2014) xxx–xxx

[99] Blackinton J, Lakshminarasimhan M, Thomas KJ, Ahmad R, Greggio E, Raza AS, et al. Formation of a stabilized cysteine sulfinic acid is critical for the mitochondrial function of the parkinsonism protein DJ-1. The Journal of Biological Chemistry 2009;284:6476–85.

[100] Yanagida T, Kitamura Y, Yamane K, Takahashi K, Takata K, Yanagisawa D, et al. Protection against oxidative stress-induced neurodegeneration by a modulator for DJ-1, the wild-type of familial Parkinson’s disease-linked PARK7. Journal of Pharmacological Sciences 2009;109:463–8.

Please cite this article in press as: Cao J, et al. DJ-1 as a human oncogene and potential therapeutic target. Biochem Pharmacol (2014), http://dx.doi.org/10.1016/j.bcp.2014.11.012