Histone deacetylation meets miRNA: epigenetics and post-transcriptional regulation in cancer and chronic diseases.

Review

1.

Introduction

2.

HDAC classes and their involvement in cancerogenesis

3.

Cooperative miRNA-HDAC

Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by University of Connecticut on 04/02/15 For personal use only.

regulation in cancer 4.

pathways of HDACs and miRNAs The analyzed pathways and their clinical relevance in detail 6.

Stefan Swierczynski, Eckhard Klieser, Romana Illig, Beate Alinger-Scharinger, Tobias Kiesslich & Daniel Neureiter† †

Paracelsus Medical University, Salzburger Landeskliniken, Institute of Pathology, Salzburg, Austria

Elaboration of the hypothesis based on shared downstream

5.

Histone deacetylation meets miRNA: epigenetics and post-transcriptional regulation in cancer and chronic diseases

HDACis in clinical trials and therapeutic possibilities

7.

Conclusion

8.

Expert opinion

Introduction: Epigenetic regulation via DNA methylation, histone acetylation, as well as by microRNAs (miRNAs) is currently in the scientific focus due to its role in carcinogenesis and its involvement in initiation, progression and metastasis. While many target genes of DNA methylation, histone acetylation and miRNAs are known, even less information exists as to how these mechanisms cooperate and how they may regulate each other in a specific pathological context. For further development of therapeutic approaches, this review presents the current status of the crosstalk of histone acetylation and miRNAs in human carcinogenesis and chronic diseases. Areas covered: This article reviews information from comprehensive PubMed searches to evaluate relevant literature with a focus on possible association between histone acetylation, miRNAs and their targets. Our analysis identified specific miRNAs which collaborate with histone deacetylases (HDACs) and cooperatively regulate several relevant target genes. Expert opinion: Fourteen miRNAs could be linked to the expression of eight HDACs influencing the a-(1,6)-fucosyltransferase, polycystin-2 and the fibroblast-growth-factor 2 pathways. Focusing on the complex linkage of miRNA and HDAC expression could give deeper insights in new ‘druggable’ targets and might provide possible novel therapeutic approaches in future. Keywords: epigenetics, histone deacetylase, microRNA Expert Opin. Biol. Ther. [Early Online]

1.

Introduction

Carcinogenesis is not restricted to genomic alterations such as amplifications, translocations, deletions and point mutations. It is also associated with epigenetic events which summarize the mechanisms of regulation of gene expression levels without alterations at the DNA sequence level. The central epigenetic mechanisms in humans are DNA methylation and post-translational histone modifications [1]. Many developmental and tissue remodeling processes such as epithelial mesenchymal transition (EMT) are epigenetically regulated by an interplay of epigenetic modifications such as DNA methylation and other ways of transcriptional reprogramming [2]. Currently, silencing of tumor-suppressor genes by promoter hypermethylation are the most widely studied epigenetic modifications in human cancers. In the last years, there was a significant increase in the knowledge and understanding of the involvement of histone modifications in cancer development [1]. The level of histone acetylation plays a crucial role in the regulation of gene transcription [3]. Histone deacetylation increases the ionic interactions between the positive histones and the negative DNA by deacetylation of "-amino groups of lysine residues in all four histone proteins in histone tails. These structural changes yield 10.1517/14712598.2015.1025047 © 2015 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted

1

S. Swierczynski et al.

Article highlights. .

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Histone deacetylases (HDAC) are overexpressed in many types of cancer such as colorectal cancer, ovarian cancer, breast cancer, pancreatic cancer and chronic disease. HDACs and miRNAs (microRNA) have been shown to interact with each other. There are distinct pathways (FUT8, PC2, FGF2) that show a HDAC-miRNA crosstalk. HDAC and miRNA driven interactions could lead to establishment of new biomarkers and new therapeutic approaches. Combination of selective HDAC inhibitors and new miRNA silencing techniques could form a new perspective in epigenetics-based therapies.

This box summarizes key points contained in the article.

to a repression of gene transcription by limiting the accessibility of the transcription system due to chromatin compaction. By histone modification, histone deacetylase (HDAC) enzymes can interact with numerous transcription factors and can regulate a large number of genes [1]. HDACs, in general, are considered to be transcriptional repressive as they stabilize condense chromosome structure and make it less accessible for transcription factors. Furthermore, these enzymes take part in co-repressor protein complexes. Apoptosis is negatively regulated by HDACs as HDAC inhibitors (HDACi) causes upregulation of proapoptotic proteins such as Bad and downregulation of antiapoptotic proteins like Bcl-2 [4]. DNA damage repair is also supported and regulated by HDACs which interact with DNA damage-responsive factors and promote DNA repair. By inhibition of the cooperating HDACs an increase of ROS (reactive oxygen species) production accompanied by suppression of DNA repair proteins is observed [5,6]. Replication of DNA requires global chromatin reconstruction which is governed by HDACs as key regulators including other aspects of cell cycle regulation via control of cyclins and cyclin-dependent-kinases. In yeast, HDACs are centrally involved in the temporal expression sequence of cell cycle genes. Accordingly, inhibition of HDACs leads to cell cycle arrest at certain phases and a delayed proliferation [5-7]. Additionally, HDACs are involved in many heterogeneous biological functions of the cell including autophagy, metabolism and heat-shock processes as well as angiogenesis: i) the influence of HDACs in autophagy which results in selfdegradation of unnecessary or dysfunctional cellular components is still under investigation; ii) HDACs have also been shown to influence metabolic processes like fatty acid metabolism, glucose utilization and oxidative phosphorylation [8]; iii) Furthermore, oncogenes and tumor suppressor genes are influenced by HDACs via the molecular chaperone heatshock protein 90; and iv) The last, currently important area of HDAC activity is the field of angiogenesis where the use 2

of HDAC inhibitors (HDACis) showed a very profound linkage to angiogenesis-stimulating factors where they block angiogenesis by downregulating angiogenesis-stimulating factor, hypoxia-inducible factor 1a (HIF-1a) and vascular endothelial growth [9]. In summary, histone de-acetylation by HDACs has been demonstrated as an important epigenetic mechanism in many research areas. In contrast, the dysregulation of cell pathways interacting with HDAC function is observed in a variety of human epithelial and hematological tumors and the therapeutic approach to treat such tumors with HDACis seems promising (Figure 1). Early clinical trials were conducted in defined tumor (sub-)types such as myeloid leukemia [10,11]. Currently, a large body of evidence indicates similarly important roles of microRNAs (miRNA) in (dys-) regulation of cellular functions in the context of cancer initiation and progression. As some of these miRNA have been shown to interact with HDAC-mediated epigenetic mechanisms, knowledge about these particular mechanisms could lead to new and meaningful combinatory treatment strategies compared to monotherapies targeting single HDACs by specific inhibitors (as discussed in Sections 6 and 7). Therefore, as many diseases share common pathways of gene or/and protein regulation by HDACs and miRNAs, a multitarget approach on HDAC and miRNA regulation could be beneficial for both, treatment of chronic diseases and cancer.

HDAC classes and their involvement in cancerogenesis

2.

The family of HDAC enzymes is divided into four classes including subclasses and comprise 18 members based on their sequence homology to the corresponding yeast HDAC [1,12]. For a better understanding of the importance of each HDAC, we first give a short description of the role of each HDAC member in human malignancies focusing on: i) target downstream pathways; ii) the tumor entity; and iii) parameters of clinical outcome (recurrence, metastasis and survival). We further give an overview of the published literature of the main HDAC members and their interactions with miRNA functions. Class I HDACs HDAC1, 2 and 3 are members of protein complexes which are necessary for transcriptional repression and epigenetic landscaping. These large multi-protein complexes silence target genes through removal of the acetyl group from the lysine residues in histone tails. In a recent series of 140 colorectal cancer samples, high HDAC1, 2, 3 expression levels were associated with a significantly shorter survival, with HDAC2 expression being an independent prognostic factor. High HDAC1, 2, 3 expressions was also associated with dedifferentiation and enhanced proliferation of pancreatic cancer cells [13,14]. 2.1

Expert Opin. Biol. Ther. (2015) 15(5)

HDACs and miRNAs

Motility (HDAC6)

Autophagy (HDAC1,6,10)

Cell cycle/proliferaton (HDAC1,2,3)

Apoptosis (HDAC1,2,4)


Immune response (HDAC1,2,6,7,11)

Angiogenesis (HDAC1,4,6,7)

Differentiation (HDAC3,8,9)

Metabolism (HDAC1,2,3)

HDAC inhibitors

DNA damage repair (HDAC1,2,3,4,6,9,10 )

• Vorinostat (SAHA) • Romidepsin • Panobinostat • Valproic acid • Belinostat • Mocetinostat • Abexinostat • Entinostat • SB939 • Resminostat • Givinostat • Quisinostat

Heat shock protein 90 (HDAC6,10)

HDACs

Figure 1. HDAC inhibitors (HDACi) and HDACs. This illustration shows the conventional areas of HDAC inhibition based on Limoene et al. with a list of FDA-approved HDACi [83]. 2.2

Class II HDACs

This class is further subdivided in two subfamilies: Class IIa is characterized by a long functionally important N-terminal domain regulating nuclear-cytoplasmic shuttling and specific DNA-binding. Class IIb contains of two tandem deacetylase domains and a C-terminal zinc finger [13]. Class IIa HDAC4 is associated with the repression of differentiationrelated genes such as Pax7 which stimulates the differentiation of satellite cells and regulates HIF-1 a transcriptional activity in renal carcinoma. HDAC5 expression has been shown to be upregulated in colorectal cancer. Its interaction with the transcription factor GATA-1 leads to murine erythroleukemia cell differentiation. HDAC7 is highly expressed in colorectal cancer, whereas it shows only moderate expression in bladder, renal and breast cancer. HDAC7 silencing in endothelial cells (EC) altered their migration and their capacity to form capillary tube like structures in vitro while it has no effect on cell adhesion, proliferation or apoptosis. This led to the conclusion that HDAC7 might be a target for anti-angiogenesis in 2.2.1

cancer therapy. HDAC9 promotes angiogenesis in EC by transcriptional repression of miRNA 17 -- 92 cluster [13-15]. Class IIb HDAC6 expression was significantly higher in squamous cell carcinoma versus normal oral squamous tissue. HDAC6 expression was correlated in breast cancer samples with better survival. High HDAC6 mRNA tended to be more responsive to endocrine treatment and was a prognostic indicator for breast cancer progression. In vitro, HDAC6 overexpression leads to an increased migration of embryonic fibroblasts while after inhibition the migration levels decreased. HDAC6 was found to play a role in epidermal growth factor-induced nuclear localization of b-catenin and subsequent c-Myc activation in colon carcinoma. HDACs 4 and 6 were shown to regulate and bind HIF-1a transcriptional activity, which is a key regulator for adaption to the hypoxic microenvironment. These two HDACs may therefore represent an important target of anti-angiogenesic therapies. Knockdown of HDAC6 and HDAC10 via siRNA transfection induced a depletion of VEGF receptor 2.2.2


3


1/2 proteins. HDAC6 is also involved in epithelialmesenchymal transition (EMT) in metastasis of bronchial carcinoma by an interaction with the TGF-b smad3 cascade. The knockdown of HDAC10 reduces VEGF receptor 1/2 expression and is involved in autophagy and the cooperation of metalloproteases 2 and 9 [13,14,16]. Class III HDACs (Sirtuins) Like other HDACs, the group of sirtuins is (over-)expressed in many types of cancer. SIRT1 is upregulated in acute myeloid leukemia, prostate and non-melanoma skin cancer, whereas it is downregulated in colorectal cancer. SIRT4 is reported to be involved in the DNA damage response pathway. SIRT3 and SIRT7 are upregulated in breast cancer. SIRT2 is downregulated in gliomas and gastric carcinoma. Up-to-now, altered expression of SIRT5 and SIRT6 in cancer has not been reported [17,18].


2.3

Class IV HDACs The loss of HDAC11 leads to cell death and inhibition of metabolic activity in ovarian cancer cell lines. Contrarily, HDAC11 is overexpressed in colon, prostate, breast and ovarian cancer cell lines [19]. In Hodgkin lymphoma, HDAC11 has been found to be involved in the regulation of OX40, which is one mediator of antitumor immunity [20]. Tumorigenic mis-regulation of HDAC expression may depend on ‘classical’ activation through DNA mutations such as point mutations. While these findings are commonly accepted, another possible regulative mechanism has been introduced by CM Wendtner in 2012: He demonstrated that inhibition of HDAC that are overexpressed in chronic lymphocytic leukemia (CLL) induces acetylation of a histone complex which influences the promoter activity of critical miRNAs involved in CLL. This finding raised the question of whether miRNAs are cooperatively linked with HDACs during tumorigenesis and how this cooperation influences downstream targets or signaling pathways. By taking up this hypothesis, the following sections summarize the available literature on HDAC and miRNA interactions and their role for carcinogenesis [21]. 2.4

Cooperative miRNA-HDAC regulation in cancer 3.

By now, the mechanisms of miRNA regulation are not fully understood. Alterations in miRNA expression in tumorigenesis and metastasis have been described within several publications. miRNAs are short, non-coding RNA molecules that influence and regulate gene expression on the posttranscriptional level. They can silence genes by binding to the 3´-untranslated region (3¢UTR) of target mRNAs, which leads to their degradation or the repression of translation. In tumor cells, specific miRNAs are down- or upregulated: for example, tumor-supressive miRNA might be downregulated during tumorigenesis, while oncogenic miRNAs (onco-miRs) 4

that target, for example, Growth-inhibiting genes are upregulated. Of special importance, it has been shown that miRNAs also regulate genes encoding for particular HDACs [11,22]. In the next paragraphs, we try to summarize current information on the complex recursive interactions between HDACs and miRNA: in particular, we focus the discussion on putatively affected downstream pathways and tumor entities associated with clinical outcome variables as far published data are available. HDAC1 The tumor suppressor miR-34, a transcriptional target of TP53, activates TP53 in a positive feedback loop via p21 (Cip1/Waf1). Interestingly, HDAC1 is a direct target of miR-34 and the repression of HDAC1 leads to an induction of p21 (Cip1/Waf1), which is mimicking the positive feedback loop as miR-34. In the absence of TP53, miR-34 is capable of inducing p21 (Cip1/Waf1). This shows that both miR-34 and HDAC1 can lead to a p21 (Cip1/Waf1) induction. Second, miR-449a is directly targeted by HDAC1 in prostate cancer tissue and this miRNA represses HDAC1 and thus growth and viability in prostate cancer cells. In summary, HDAC1 and miR-34 or miR-449a interactions are linked to cell cycle arrest, apoptosis and senescent-like phenotype via cell-cycle-dependent kinase inhibitors like p21 (Cip1/Waf1) or p27 (Kip1) as well as other related proteins such as p53, PUMA, bcl-2, CDK6 or Sirt1 [23-25]. 3.1

HDAC2 The depletion of HDAC2 in neuroblastoma models caused an increased miR-183 expression. This could also be mimicked by treating neuroblastoma cell lines with small molecules inhibiting HDAC2 enzyme activity. Complete HDAC2 depletion increased histone H4 pan-acetylation of the miR-183 promoter region indicating increased transcriptional activation which leads to a tumor suppressive effect through miR-183 in neuroblastoma. The molecular linkage between HDAC2 and miR-183 is the proto-oncogen MYCN regulating the transcriptional activation and repression of multiple genes involved in human cancerogenesis [26]. 3.2

HDAC3 Knockdown of HDAC3 with specific siRNA results in an increased hyperacetylation of the Dleu/miR-15a/16-1promoter region. This upregulation increased the expression of miR-15a/16-1, which suppressed cell growth and colony formation in lung cancer cells, which is obviously regulated via Bcl-2, a master anti-apoptotic gene. In hepatocellular cancer, inhibition of HDAC1 and HDAC3 significantly enhanced the transcription of miR-224 leading to increased cell proliferation and apoptosis as well as cell migration and invasion in liver cells [27,28]. 3.3


HDACs and miRNAs


3.4

HDAC4

In B-cell leukemia, miR-155 directly targets HDAC4 a corepressor of Bcl-6 which regulates the expression and activity of Bcl-6 by promoting cell survival and proliferation markers such as inhibitor of differentiation (Id2), IL-6 (IL6), cMyc, Cyclin D1, and Mip1a/ccl3 [29]. Additionally, miR-206 inhibits HDAC4 in mice muscle cells; this affects the endogenous levels of HDAC expression in the mouse model modulating the myogenic differentiation via the TGF-b-signaling pathway as already shown for HDAC3 [30,31]. Several miRNAs were characterized to modulate HDAC4 including miR-1, miR-29, miR-140, miR-200a and miR-365 in different cell types. MiR-200a directly targets the 3¢-UTR of the HDAC4 mRNA and represses expression of HDAC4. MiR-1 and miR-499 in cardiomyocyte progenitor cells reduced proliferation rate, and enhanced differentiation into cardiomyocytes in human cardiomyocyte progenitor cells and embryonic stem cells via the repression of HDAC4. MiR-29 has been implicated in muscle differentiation is downregulated by TGF-b. TGF-b treatment of myogenic cells is associated with increased expression of HDAC4. MiR-365, a mechanically responsive miRNA, was associated with modulation of chondrocyte differentiation via directly targeting HDAC4 and miR-140 demonstrated the phenotype of dwarf as a consequence of impaired chondrocytes [32]. HDAC5 HDAC5 is targeted by miR-2861 in osteogenesis. The relevant downstream pathway partner of both is the bone morphogenetic protein 2. Experimental regulation of HDAC5 and miR-2861 is linked to primary osteoporosis in humans [33]. 3.5

LAMC1 and PAX6 in tongue squamous cell carcinoma (TSCC). Therefore, the HDAC7 and miR-140-5p-associated extracellular matrix interactions via ADAM10 influence the invasive and migrative potency of TSCC [37]. HDAC8 In human colon cancer stem cells, negative regulation of HDAC8 via miR-93 suppresses proliferation and cell colony formation [38]. Thereby, the repressive effect of miR-93 on HDAC8 is paralleled with other miRNA targets such as BAMBI, CCND2, CDKN1A, KIF23, MAP3K9, MAP3K11, MYCN, PPARD, TLE4 and ZDHHC1. The mentioned pathways are partially linked to the APC/b-Catenin-pathway, for example, BAMBI (Akiyama et al. 2004), CDKN1A (Ben-Neriah et al. 2011), MCYN (Yochum et al. 2014), PPARD (Faivre et al. 2002) and TL4 (Jones et al. 2006) indicating how HDAC and miRNA is cooperatively linked to colorectal cancer by downstream interactions of different sub-pathways [39-43]. 3.8

HDAC9 HDAC9 regulates miRNAs in EC as silencing of HDAC9 stopped sprouting in vitro and reduces vessel growth in a zebrafish model in vivo. The pro-angiogenic effect of HDAC9 is mediated by repressing the miR-17-92 cluster. The endothelial cell tube formation and sprouting is linked to the JAK-1 pathway which could be used as possible common therapeutic target in cancer vasculogenesis [44]. 3.9

HDAC10 Until now, no miRNA data are published (01/2015). 3.10

HDAC11 Downregulation of miR-145 by IFN-I targets HDAC11 and leads to increased IL-10 expression in macrophages. This crosstalk between HDAC11 and miR-145 via IFN-I and IL-10 influences the innate immune response which is linked again with the JAK1-Stat1 signal cascade in HDAC9 [45]. To summarize these published data, inhibition of miRNAs and their influence on the HDACs showed similar or better effects on the cellular effects (like proliferation/apoptosis, inflammation/immune response, differentiation/motility -- see Figure 1) compared to the inhibition via HDAC inhibitors. As reviewed by Shi et al., it could be postulated that by using proper biomarkers, identifying tumors and stratifying patients into groups that may undergo an improved clinical response to HDAC inhibitor-based therapy we can make an individual therapy for the benefit of the patients, although it would gain more precision to incorperate miRNAs, too [46]. In 2012, La Thangue et al. suggested that rationally designed therapy in different types of cancers, probably in combination with other anticancer agents for targeting the pathway for each type of HDAC could be promising for development of more effective therapies [47]. From these thoughts combined with the abovementioned known associations of miRNA and HDAC 3.11

3.6

HDAC6

In a case report of a family with X-linked dominant chondrodysplasia, it was shown that this gene variant is located in the HDAC6 genomic sequence matching the seed of miR-433. This HDAC variant completely abrogates the posttranscriptional regulation normally exerted by this miRNA on an HDAC6 3¢-UTR-bearing transgene in transduction experiments. The pathogenetic effect of HDAC6 inhibition via has-miR-433 is an increased level of a-tubulin associated with decreased histone acetylation at the a-tubulin locus [34]. MiR-22 acts as a critical regulator of balance between adipogenic and osteogenic differentiation of human adipose tissue-derived mesenchymal stem cells by repressing its target HDAC6 [35]. Increased expression of miR-548 by ectopic miR-548 expression leads to a downregulation of HDAC6 mRNA and protein expression in lymphoma cells. In contrast, knockdown of miR-548 by transfection of antimiR-548 increased HDAC6 expression [36]. HDAC7 HDAC7 is a direct target of miR-140-5p, which plays a role in inhibition of migration-related genes such as ADAM10, 3.7


5



• Literature combinations of HDACs and miRNAs. • miRNA from the literature searched for their target genes.

2. Searching cycle • Target genes searched for other miRNAs. • HDACs searched for their theoretical target miRNAs from databases (mirbase.org/ DIANAMICROT).

1. Searching cycle

• Combination of the miRNAs from the HDACs, the target genes and their miRNAs as well as the miRNAs from literature search. • Literature query for documented conformities.

Final step

Figure 2. Strategies for data mining and database search (PubMed, mirbase.org and DIANA-MICROT).

functions, we propose that combined inhibitory strategies targeting both these epigenetic regulators might be especially worth exploring in future research. 4. Elaboration of the hypothesis based on shared downstream pathways of HDACs and miRNAs

For substantiation of our hypothesis of a multitarget therapy based on simultaneous inhibition of HDAC and miRNA function, PubMed was searched for literature to investigate any published linkage between HDACs and miRNAs. We searched in two different miRNA and gene databases (mirbase.org and DIANA-MICROT) for overlap of the published HDAC-miRNA combinations within their theoretical gene output and classified the results in three categories: i) direct interaction of miRNAs and HDACs; ii) the interaction of these miRNAs on targets (genes); and iii) and the genes that directly or indirectly interact with HDACs. As outlined in Figure 2, combination of HDACs and miRNAs were searched in the first step of data mining, combining target genes of both players in the second step and the consecutive pathways were characterized for the association of HDACs and miRNAs (Figure 2). These three overlapping queries led to an index (Figure 3) where we collected all miRNA target genes of every HDAC (database software DIANA-MICROT v3.0) with a precision almost higher than 0.8 in the database. After detailed consideration, we formed a hypothesis on the connections of HDACs with their miRNA targets and vice versa. This formed a cycle of regulations between genes, HDACs, miRNAs and the attached protein expression 6

(illustrated in Figure 4), which shows the perceptual weighting of direct and indirect linkage between HDACs and miRNAs in the literature. In comparison to the current literature, which rather describes indirect regulation (ii/iii) effects of HDACs and miRNAs, available data on the direct regulation (i) is scarce as also mentioned by Noonan et al. as well as by other authors [23,48-51]. Figure 4 illustrates that there is evidence that the regulation of HDACs and miRNA is linked on different molecular levels as shown by Delcuve et al. [52]. To substantiate this hypothesis, we searched in every direction of the regulatory HDAC-miRNA cycle in order to find evidence for such connections. We searched all sides of HDAC interaction, although direct or indirect with miRNAs and their targets (genes/proteins) and after that we filtered only the few that give a complete signaling cycle out. The remaining genes were again searched in PubMed for the published data to validate our hypothesis [52,53]. For the first data set, we searched for any evaluated HDAC and for all genes displayed in Figure 3. We looked for both, the estimated miRNA targets and the one connected with them. After that we did another literature search for the 12 genes that displayed a HDAC-gene couple. The a-(1,6)-fucosyltransferase 8 (FUT8), polycystin 2 (PC2) and fibroblast-growth-factor 2 (FGF2) pathways revealed a prominent connection by database and literature search and were selected for further investigation (whole search list not shown due to the extensive data set of genes). All three genes (Figure 5A -- C) demonstrated a function in proliferation and could be linked with regulation of growth factors.


mir15a

mir224

HDAC3

HDAC3


mir17

HDAC9

Traget Genes Functional Areas Sirt1 SATB2 Apoptosis ZNF281 TGIF2 Receptor Function (GABA) GABRA3 BRPF3 Malignancy/Invasivness FUT8 E2F3 Oncogenic Transformation RRAS Protein Modification FAM76A Development FAM70A Cell Cycle Modulation ACSC4 Development (Cleft Palate) GOLPH3 Mitotic Cycle CPEB2 SALL1 Translation CCNE1 KIF23 Mitotic Cycle FGF2 WIPI2 Growth Factor PLAG1 AKT3 Development WEE1 C1ORF21 Organelle Transport STOX2 Multiprotein Complex SLC20A2 STK33 ZBTB34 C2ORF21 API5L1 Histone Acetyltransferase Nuclear Transcription MYST3 API5 Oncogenic Transformation AFF3 YOD1 Mitochondrial Membran AFF2 UBE2D3 Apoptosis KCTD12 DDX34 Ubiquitin Ligation BAZ2A FAM49B MARCH5 GGNBP2 XKR3 SLMAP Extracellular matrix FNDC3A HIVEP3 Migration RNF165 NRP1 Differnetiation GJA1 CD2AP Angiogenesis TNKS2 SFRS9 Invasion FNDC3B RNA Binding UST Transcription Factor TMSB4X Splicing Factor HNRNPU Gap Junction CAGE1 Cell-Cell Contact RNF165 C11ORF61 Actinremodeling FNDC3A RSBN1 Alternative Splicing TNKS2 CAGE1 GJA1 CD2AP UST HNRNPU HIVEP3 TMSB4X SFRS9 Mitotic Cycle TITY5 AP3B1 Development UBR1 SAT1 Neuronal Excitability CEP135 PDZRN3 EPHA7 ZC3H6 C2ORF3 KCNIP2 SORBS CHD9 TTC8 Development SERF1A E2F5 Oncogenic Transformation SERF1B C7ORF43 MAPK-Pathway ZNFX ITGB8 Cell-Cell Contact PLEKHA3 VSX1 Polycystic Kidney Disease SCC35E2 SLITRK3 MYCN PKD2 MAP3K2 GPR137C MAP3K9 Growth Factors SNX2 RNF19A Leucine Zipper Factor Family GPR161 HAND2 Cardiac Morphogenesis MMD ZNF800 Immunoglobulin Superfamily C15ORF29 GALNTL1 Sorting Nexin Family TSSK2 CNTN1 BCL11A G-protein coupled receptor 161 PDGFRA YOD1 C14ORF101 BACH1

HDAC Member miRNA

Traget Genes FUT8 E2F3 RRAS LEF1 HDAC1 mir449a ZNF281 SYT1 SATB2 SLC25A27 GABRA3 FAM76A GOLPH3L FAM70A TGIF2 Breast Cancer PSEN2 LRP6 Chronic Lymphotic Leukemia DUSP10 PTPN4 Myeloid Leukemia HDAC2 mir183 PFN2 PPR2CB Ovarian Carcinoma PPR2CA SAC5 Basal Ganglia Calcification KCNK10 GNG5 Tones-Brock Syndrome TMPO Glioma AKAP12 MAL2 BTG1 Myeloid Leukemia ZNF585a ZNF678 Diabetes Type2 GMFB ZNF283 Parkinson HDAC3 mir16 ZNF588 GOLGA7 ZNF107 GOLGA8G ZNF117 GOLGA8F ZNF138 SEPT2 HDAC1/7a IKZF2 WDR72 RNF6 Multiple Sclerosis JARID2 LDLRAD3 Urinary Bladder Carcinoma TSHZ3 MBTD1 Parkinson HDAC4 mir155 IRF2BP2 ZBTB38 Melanoma RNF123 DUSP14 Colorectal Cancer WEE1 FGF7P2 DHX40 FGF7 LRP1B ARID2 FOS Multiple Sclerosis SIRPA PALM Parkinson PTPRC Arthritis HDAC5 mir2861 COLEC10 Urinary Bladder Carcinoma PI3 Alzheimer Disease FAM62A Interstitial Fibrosis Disease GRIK2 RRBP1 CLIP3 HOXB4 Alzheimer Disease SERF1A TNKS2 Johanson-Blizzard Syndrome SERF1B MAGI3 Glioblastoma HDAC8 mir93 MYCN RAB11FIPS Hyperpigmentation ZVFX1 GPR6 Cardiac Disease PLEKMA3 MYT1L Foot-and-Mouth Disease MAP3K2 mir183 SLC35E2 GPR137C HDAC2 SLITRK3 Neuroblastoma ATN1 CLCN6 Pulmonary Hypertension PPME1 TNPO1 Lung Cancer HDAC9 mir92 BCAM NANP Ovarian Cancer ZBTB34 DRP2 Synapse Development ZNF3 PPFIA4 Polycystic Kidney Disease HKR1 MB SIX4 WFDC2 TPP1 Leukemia DST LGALS14 Thyroid Disorders ATRX Lung Cancer HDAC11 mir145 GRIK2 Proliferative Vitreoretinopathy SMG7 Breast cancer PDZK1P2 Hears Disease PRAMEF19 Squamous Cell Carcinoma PDZK1 RAD51AP1 SHOC2 NFIA All data were collected with mirbase.org and evaluated with DIANA-MICROT.

Clinical Relevance Alzheimer Disease Blood Pressure Pulmonary Emphysema Huntington Disease Hepatocellular Carcinoma Osteoporosis Prostate cancer

Myeloid Leukemia Huntington Disease

Zinc Finger Protein Glia Maturation IKFZ2+IKFZ1--Hdac7a, Hdac1 Golgi Organisation DNA Damage Response

Panceatic Neuroend. Tumor Noonan-Syndrom Myeloid Disease

Huntington Disease Alzheimer Disease Sickle Cell Disease Ovarian Cancer Neuronal C. Lipofuscinosis

Exctracellular Matrix Modulation Transcription Factor Lysosome Function Ion Chanel Regulation

Chromatin Remodeling DNA Repair Transcription Factors Membrane Regulation

Neuroblastoma Neuropsychiatric Disorders Colon Cancer Alzheimer Disease Depression

Melanoma Leukemia

Development Ras Pathway Oncogenic Transformation MAPK Pathway PTEN Interaction Transmembrane Signaling

Growth Receptor Signaling Mitotic Cycle Oncogenic Transformation RNA Editing mRNA Modulation Development

Myeloid Leukemia Depression Ovarian Cancer Alzheimer Disease Pulmonary Disease

Alzheimer Disease Huntington Disease Ovarian Cancer Colorectal Cancer Thyroid Carcinoma

Cell growth (MAPK/ERK/PKA) Actin Polymerization Regulation of Ca/K CD90 Induction Transcytose WNT-Signaling (LRP) Mitotic Cycle Oncogenic Transformation

Cell Proliferation Neural Development Mitotic Cycle Cellular Processes (Splicing) LDL Receptor Cell Survival Environmental Stress

Clinical Relevance Pulmonary Emphysema Huntington Disease Colorectal Cancer Osteoporosis Hepatocellular Carcinoma Glioblastoma Lung cancer

Functional Areas Ras Pathway Zinc Finger Protein Development (Cleft Palate) Neurotransmitter Golgi Organisation Oncogenic Transformation Mitotic Cycle

Figure 3. Overview of data mining results. This figure shows the regulations between HDACs and distinct miRNAs including common (?) target genes. The functional areas and the clinical relevance indicate possible therapeutic fields for several cancers including lung and breast cancer as well as neuropsychiatric disorders such as depression.

? HDAC7

HDAC2

? mir140

mir433

HDAC6

mir183

mir1

HDAC4

HDAC4

mir206

mir34

HDAC1

HDAC1

miRNA

HDAC Member


HDACs and miRNAs

7


Direct regulation between HDAC – miRNA (10% of literature)

HDAC

Indirect regulation through gene – protein level (90% of literature)


miRNA Genes ↑↓ Proteins ↑↓

Figure 4. Distribution of direct and indirect regulation within the miRNA-HDAC axis. This illustration places special emphasis on indirect regulations between HDACs and miRNAs. Additionally, a few studies prove a direct interaction which demonstrate that both ways of HDAC-miRNA regulation are possible (see Figure 3 for details) [23,48-51]. 4.1

FUT8 pathway

FUT8 is attached with HDAC1 and HDAC2 which are imparted over the miR-34a which is described to be involved in p53 interaction [54-59]. PC2 pathway PC2 is closely connected with the miRNA cluster 17 -- 92, and this cluster is regulated by HDAC9. The silencing of HDAC9 in EC increased the expression of miRNA cluster 17 -- 92. Furthermore, the inhibition of miRNA cluster 17 -- 92 rescued the impairment of EC sprouting induced by HDAC9 silencing in culture and partly reversed the effect. MiRNA cluster 17 -- 92 is also the link between HDAC9 and BMPR2 [60-63]. 4.2

FGF2 pathway FGF2 is in a very central position in the cycle and is counter affected from the HDAC1/9 and also HDAC3. FGF2 also is regulated indirect over miRNA-15a, which is connected with HDAC3 [64]. 4.3

The analyzed pathways and their clinical relevance in detail 5.

a-(1,6)-fucosyltransferase 8 (FUT8) The FUT family is involved in cell-surface antigen synthesis during various biological processes such as tumor multi-drug resistance (MDR). Cheng et al. showed in hepatocellular carcinoma cell lines (HCC) that the members of the FUT family were highly expressed in MDR cell lines [65]. 5.1

8

The altered level of FUT8 was involved in a change of the drug resistance of the cells. The regulation of FUT8 had an impact on the phosphoinositide 3 kinase (PI3K)/Akt signaling pathway [65]. Tonetti et al. showed in hepatocarcinoma cell lines that forced expression of miR-122 and miR-34a is able to induce a decrease of FUT8 levels and also to affect core fucosylation of secreted proteins [66]. Fang et al. showed that overexpression of miR-198 in CRC cell lines decreased FUT8 levels as shown by immunofluorescence analysis and inhibited cell proliferation, migration and invasion [67]. Polycystin-2 pathway Polycystin-2 (PC2) is emerging as a major player in mechanotransduction and therefore relevant for tumor cellular invasion and metastasis during cancer progression. The protein expression of PC2 in colorectal cancer showed that its overexpression results in upregulation of the mTOR pathway and PC2 overexpression is connected with unfavorable pathological parameters, including invasiveness and mucinous phenotypes. Low expression of PC2 leads to an overall poor survival [68]. Dysregulated miRNA expression is observed in PC2, but whether miRNAs are directly involved in kidney cyst formation and growth is not known. Igarashi et al. show that kidney-specific inactivation of miR-17-92 in a mouse model of PC2 retards kidney cyst growth, improves renal function and prolongs survival [69]. As reviewed by Li et al., pharmacological inhibition of HDAC 6 and 5 activities reduces the progression of cyst formation and slows down the decline of kidney function in PC1-conditional knockout mice and PC2-knockout mice [70]. 5.2


HDACs and miRNAs

A.

TP53 HDAC1 mir-34a

a-(1,6)fucosyltransferase 8

mir-449a FUT8

mir-3148

mir-34a


HDAC2

• Responsible for α1,6-fucosylation of N-glycans • Core fucosylation has been demonstrated to be essential for signaling of several growth factors and adhesion molecules, such as EGF, E-cadherins, TGF-β, and integrins • Activity and expression are increased in colorectal cancer and hepatocarcinoma cells

C.

B. HDAC8

BMPR2

mir-15a HDAC9

mir-3143

mir-17(-92 cluster)

HDAC 1/9

HDAC3

mir-3163

mir-16

PKD2

Polycystic kidney disease (polycystin 2) Fibroblast growth factor 2

• Presence of numerous fluid-filled cysts in the renal parenchyma • Cyst epithelial cells secrete excessive fluid • Monogenic human diseases • Proliferation

FGF2

• Proliferation • Wound healing • Differentiation

Figure 5. Detailed interaction map of HDAC and miRNAs. A. Regulation of FUT8: a-(1,6)-fucosyltransferase 8 is regulated by three miRNAs (mir-34a, mir-449a, mir-3148) which are connected with HDACs 1 and 2. HDAC1 and mir-34a are also involved in the feedback loop regulation with TP53 over p21 (Cip1/Waf1) for cell cycle control [54-59]. B. Regulation of PKD2/PC2: The cycle of PKD2/PC2 shows an involvement of the miRNA cluster 17 -- 92 which regulates HDAC9 and acts by repression of proangiogenic factors. The cluster is also involved in BMPR2 signaling which is connected to metastasis in breast and colorectal cancer [60-63]. C. Regulation of FGF2: The regulation of FGF2 is mainly performed by mir-16 and mir-15a which are in a feedback loop with HDAC3. HDAC 1 and HDAC9 play only secondary roles in FGF2 regulation through mir-3163 but may also be important as a therapeutic target [64].

5.3

Fibroblast growth facter-2 pathway

Fibroblast growth factor-2 (FGF-2) is an important trigger for EMT. In particular, FGF-2 triggers the motility of proximal tubular epithelium cells through the expression of vimentin (VIM) and a-smooth muscle actin (SMA), release of matrix metallopoteinases 9 and 2 and reduced expression of

cytokeratin and E-cadherin in proximal tubular epithelium. Intracellular signaling by FGF-2 is transported via the MAP kinase pathway, the PI3K/akt pathway and the phospholipase C g pathway. The PI3K/Akt pathway has been linked direct to FGF-2-induced EMT [71]. Bonci et al. showed that downregulation of miR-15 and miR-16 in cancer-associated


9


Table 1. Overview of current clinical trials and possible miRNA targets, based on [84-92]. Clinical trial phase appr.

III

HDACi

HDAC classes or HDAC members

Vorinostat I, II(a,b), IV (SAHA) Romidepsin 1, 2, 4, 6 Panobinostat I, II(a,b), IV Valproic acid I, IIa


II

Belinostat Mocetinostat Abexinostat Entinostat SB939 Resminostat Givinostat Quisinostat

I, II(a,b), IV 1, 2, 3, 11 I, IIb 1, 2, 3, 9 Unknown Unknown I, II Unknown (Takai et al. 2010)

Related miRNAs miR-19a and miR-19b (Altucci et al. 2013)/miRNAs 21 and 17 -- 92 (Humpreys et al. 2013) n.a. miR-19a, miR-19b1, mir-30a (di Fazio et al. 2013)/miR-15a and miR-16 (Keating et al. 2012) miR-129 (Stamm et al. 2013)/miR-331 and miR-885-3p (Chuang et al. 2012)/ miR-16a, 18c, 122, 132, 457b, and 724 (Hahn et al. 2013) n.a. n.a. miR-21 (Kiguchi et al. 2012) miR-125a, miR-125b, and miR-205 (Liu et al. 2013) n.a. n.a. n.a. n.a.

appr.: FDA-approved; HDACi: HDAC inhibitors; n.a.: No data available.

fibroblasts in prostate tumors promoted tumor growth and progression through reduced post-transcriptional repression of FGF-2 and its receptor FGFr1, which act on both stromal and tumor cells to enhance cancer cell survival, proliferation and migration [72]. The three pathways FUT8, PC2 and FGF2 contribute together with the important stages of the hallmarks of cancer for drug resistance, invasiveness and transformation postulated by Weinberg and Hanahan [73].

Sungkwan An et al. reviewed that treatment of human lung epithelial cells with vorinostat significantly changes the miRNA expression in this cell type and evaluated the profile of several regulated miRNAs in detail [79]. Combination of HDACis with miRNA inhibition is not yet established in any clinical trial, and based on the data summarized in this review, this approach is highly interesting to establish a new therapies for diseases associated with specific deregulations of HDACs and miRNAs [79].

6. HDACis in clinical trials and therapeutic possibilities 7.

HDACis are used as anticancer agents that inhibit all functional processes of HDACs [74]. They have emerged as powerful new class of small molecule inhibitors for modulation the acetylation state of histone proteins and none-histone proteins. Over 490 clinical trials have been initiated in the last 10 years but only a few in Europe and the US are actually concerning possible interactions on miRNAs [75]. HDACis cause apoptosis, differentiation and cell growth arrest both in vitro as well as in vivo. The HDACis are divided in four chemical classes: hydroxamic acid derivatives, cyclic peptides, short-chain aliphatic acids and benzamides (summarized in Table 1) [76]. As an example for a current cell culture study, the HDACi vorinistat showed in the human colon cancer cell line (HCT116) with or without p53 changes in the miRNA expression of 144 miRNAs out of 275 target miRNAs. [77]. In colorectal cancer cells, the miRNAs 21 and 17 -- 92 clusters have oncogenic properties, and Humpreys et al. demonstrated that vorinostat resulted in a decrease in cell growth associated with altered expression of these particular miRNAs [78]. 10

Conclusion

HDACs and miRNA are interconnected, which indicates that epigenetic regulation and post-transcriptional regulation play an important role and influence each other in various ways during cancerogenesis. Additionally, HDACis are reported to influence the expression levels of a defined number of miRNAs. The feedback between miRNAs and HDACs often plays an important role in cancer progression and cancer inhibition. This knowledge could lead to specific cancer therapies, which would employ HDACis and simultaneously modify miRNAs. Many HDACs showed interactions with a variety of miRNAs in many different human malignancies, and in each case, the modulation of these led to significant changes in cancer progression. Silencing of miRNA by the hypermethylation of CpG islands of tumor-suppressor miRNAs contributes to cancerogenesis and methylation signatures of miRNAs are associated with metastasis. Therefore, it might make sense to evaluate these methylation signatures to detect new biomarkers for therapeutic applications in the future [11,22,80-82].


HDACs and miRNAs


8.

Expert opinion

Biomarker determination should be the first step to tailor a personalized treatment for each and every patient (Illig et al. 2013). The observation of miRNA and HDAC interactions in cancer progression and drug resistance should be evaluated for combination treatments. There are an increasing number of clinical trials with HDACis in different tumor entities (e.g., lymphoma, pancreatic cancer) in Phases I to III, whereby possible miRNA crosstalk is currently analyzed only in a limited number. In these trials, miRNAs play only a secondary role in the evaluation of clinical parameters which are directly affected by HDACis. Interestingly, several in vitro studies showed a relevant interaction of HDACs and miRNAs involved in established cancer-associated pathways (e.g., TGF-b-signaling, APC/b-Catenin pathway, MYC pathway and cell-cycle signaling [p21]). This justifies studying these two possible partners in the context where they interact with each other during tumorigenesis. As already shown by our group (Kiesslich et al. 2014), combination of small molecule inhibitors of the hedgehog pathway and conventional chemotherapeutics could open new therapeutic windows in orphans and lethal cancer disease such as biliary tract cancer. We are aware that the non-histone modifications by HDACs could complicate this simplistic view of our hypothesis, see also Stintzing et al. 2011. In our opinion, the combination of silencing specific miRNAs in combination with approved HDACis could be a very promising approach in the field of epigenetic therapy. Furthermore, the mentioned HDAC and miRNA interaction partners could serve as additional biomarkers to stratify patients with particular chronic diseases and cancer types for optimal therapeutic outcome. For this approach, still more specific and also clinically approved HDACis are needed as well as better ways to directly target miRNAs. As discussed by Faroogi et al. 2014, specific targeting of miRNAs is a Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Affiliation Stefan Swierczynski1,2, Eckhard Klieser2, Romana Illig2, Beate Alinger-Scharinger2, Tobias Kiesslich3,4 & Daniel Neureiter†2 † Author for correspondence 1 Paracelsus Medical University, Salzburger Landeskliniken, Department of Surgery, Salzburg, Austria 2 Paracelsus Medical University, Salzburger Landeskliniken, Institute of Pathology, Salzburg, Austria Tel: +0043 0662 4482 4737; Fax: +0043 0662 4482 882; E-mail: [email protected] 3 Paracelsus Medical University, Institute of Physiology and Pathophysiology, Salzburg, Austria 4 Paracelsus Medical University, Salzburger Landeskliniken, Department of Internal Medicine I, Salzburg, Austria

Epigenetic modulation of chronic anxiety and pain by histone deacetylation.

Epigenetics meets immune checkpoints.

Wnt signalling meets epigenetics.

Histone demethylases and their roles in cancer epigenetics.

Posttranscriptional Regulation and RNA Binding Proteins in Cancer Biology.

Histone deacetylation: establishing a meiotic histone code.

Epigenetics meets metabolism through PHB-mediated histone H3.3 deposition by HIRA.

Nutrition, epigenetics, and diseases.

Beyond the histone tale: HP1α deregulation in breast cancer epigenetics.

Epigenetics and Autoimmune Thyroid Diseases.

Vascular histone deacetylation by pharmacological HDAC inhibition.

Cancer epigenetics: now harvesting fruit and seeding for common diseases.

TGFbeta and miRNA regulation in familial and sporadic breast cancer.

The miRNA-mediated cross-talk between transcripts provides a novel layer of posttranscriptional regulation.

Role of messenger RNA subcellular localization in the posttranscriptional regulation of human histone gene expression.

Epigenetics in ocular diseases.

Epigenetics: Disrupting histone lysine methylation.

Characterization and miRNA-mediated posttranscriptional regulation of vitelline membrane outer layer protein I in the adult chicken oviduct.

Regulation of genes related to immune signaling and detoxification in Apis mellifera by an inhibitor of histone deacetylation.

Impact of miRNA sequence on miRNA expression and correlation between miRNA expression and cell cycle regulation in breast cancer cells.

Regulation of miRNA processing and miRNA mediated gene repression in cancer.

Epigenetics: Histone methylation: it's in the numbers.

Epigenetics and Triplet-Repeat Neurological Diseases.

[Epigenetics in inflammatory systemic diseases].