Mol Biol Rep (2014) 41:233–240 DOI 10.1007/s11033-013-2856-0
Transcriptional regulation of the survivin gene Romain Boidot • Fre´de´rique Ve´gran Sarab Lizard-Nacol
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Received: 20 December 2012 / Accepted: 30 October 2013 / Published online: 7 November 2013 Ó Springer Science+Business Media Dordrecht 2013
Abstract Survivin, a small member of the inhibitors of the apoptosis protein family, is highly deregulated in cancer. It is weakly expressed in normal tissues but very strongly expressed in malignant lesions. Survivin is involved in cell-cycle progression, especially in the G2/M transition, and has anti-apoptotic activity, which correlates with its strong expression in cases with a poor cancer treatment response and poor outcomes. Several therapies that target the survivin transcript or protein are currently being tested in clinical trials. However, focusing new therapies on the origins of survivin overexpression and targeting these upstream deregulations could be more effective. For this reason, it seems important to make an inventory of the transcriptional (de)regulation of survivin. This review will gather the important points concerning the regulation of survivin mRNA expression: structure of the survivin promoter, epigenetic modifications and genetic abnormalities, transcription factors, and signalling pathways that affect survivin mRNA expression.
Introduction Survivin contains only one BIR (Baculovirus IAP Repeat) domain and is involved in cell-cycle progression and apoptosis inhibition. The human survivin gene, named birc5, consists of 4 exons and 3 introns spanning 14796 nt on chromosome 17q25 [1]. Its alternative transcription gives rise to five different transcripts: survivin, survivin-DEx3, survivin3B, survivin-2B and survivin-2a. Survivin is periodically expressed during the cell cycle. Its expression is weak in G1, multiplied by 6 in the S phase and by more than 40 in G2/M [2]. Survivin is weakly expressed in normal adult tissues but is highly expressed in many cancers such as breast, colon and lung cancer [1, 3]. In cancer cells, the main role of Survivin is the inhibition of apoptosis. Its overexpression greatly inhibits cell death, whereas its down-expression induces massive apoptosis in response to cytotoxic drugs.
Survivin mRNA expression in normal cells Keywords Transcription factors Genetic alterations Signalling pathways survivin gene Transcription regulation
R. Boidot (&) F. Ve´gran S. Lizard-Nacol Unit of Molecular Biology, Centre Georges-Franc¸ois Leclerc, 1, rue du Professeur Marion, 21079 Dijon Cedex, France e-mail: [email protected] F. Ve´gran Faculte´ de Me´decine, Equipe AVENIR, Inserm U866, Dijon, France
Survivin is strongly expressed in cancerous tissues but its expression is also detected in normal tissues [4, 5], especially in myeloid stem cells, umbilical cord blood CD34? cells, peripheral blood mononuclear cells and T lymphocytes [6, 7]. These last two studies highlighted the fact that survivin was expressed at all stages of the cell cycle and not only at the G2/ M transition, and that growth factor stimulation of CD34? cells induced an increase in survivin mRNA (and protein) expression. In addition, the activation of naive T lymphocytes induced increased survivin expression, which correlated with cell proliferation [6]. The same phenomena were recently observed in normal dividing cells [8]. Survivin expression is indispensable for the G2/M transition. The increase in survivin expression at this phase
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could be explained by the lifting of inhibition that occurs during the G1 and S phases. Indeed, Cyclin-Dependent Kinase 4 CDK4 is only active during the G1 and S phases. Activated CDK4 phosphorylates Rb, which binds the survivin promoter and represses its activity [9]. In G2, CDK4 is inactivated and Rb is not able to repress survivin promoter activity, thus inducing an increase in survivin expression for the G2/M transition. Over the years, the cancer specificity of survivin has been called into question. It appears that survivin is undoubtedly overexpressed in cancer tissues, where it plays a critical role in cancer progression. Nevertheless, as we have seen, its expression also seems very important in normal cells, especially for cell-cycle progression. These observations tend to indicate that the direct targeting of survivin could have dangerous side effects by also affecting normal cells. The involvement of survivin in normal cell-cycle progression indicates that the targeting of survivin should be indirect and achieved by inhibiting proteins or pathways involved in its high expression in cancer cells. Survivin promoter specificities (Fig. 1) The survivin promoter possesses a canonical CpG island and numerous Sp1 sites but no TATA box [1]. Among the numerous Sp1 sites, three are indispensable to gene transcription: -171, -151, and -140 [10]. The survivin proximal promoter also contains 3 CDE (Cell-cycle Dependent Element) at -6, -12, -171 and one CHR (Cell-cycle gene Homology Region) at -42. Both kinds of sequences are characteristic of genes expressed during G2/M and allow the periodicity of the cell cycle via an interaction with CDF-1 (Cycling DOF Factor 1), a G1 regulator protein.
Fig. 1 Proximal survivin promoter specificities. Solid red lines correspond to Sp1 sites and asterisks represent indispensable Sp1 sites for survivin expression. Solid blue lines highlight CDE regions and dashed blue line correspond to CHR sequences. Transcription factor binding sites are indicated in purple. SNP sequences are indicated with green lines. Bold arrow shows the transcription start and the ?1 points out the translation start codon. (Color figure online)
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Moreover, it has been shown that a C/G polymorphism at -31, located in the CDE/CHR repressor element, was a genetic defect found in tumour cells but not normal cell lines, and that this polymorphism correlated with increased survivin expression. This change may inhibit the binding of specific proteins on CDE elements and thus lead to the derepression of survivin transcription [11], though in breast carcinoma, this polymorphism does not influence survivin expression [12]. However, at the -235 site, a G/A sequence is strongly associated with survivin expression in breast carcinoma. The presence of an A at -235 creates a GATA-1 transcription factor binding site that induces survivin expression by the interaction between GATA-1 and the survivin promoter [5]. The specific features of the survivin promoter could explain its expression profile observed in normal cells. Indeed, specific sequences such as CDE and CHR directly influence its specific expression in G2/M. Moreover, as GATA-1 is a transcription factor expressed in red blood cell precursors and survivin is required for good erythroid differentiation [13], we can imagine that individuals with G/A may have a greater number of red blood cells than do individuals with G/G. Nevertheless, the deregulation of survivin gene expression in cancer is a consequence of different alterations, including epigenetic modifications and genetic abnormalities.
Epigenetic modifications and genetic abnormalities The survivin gene has a CpG island in exon 1 [1], which is possibly involved in the regulation of its expression. In ovarian cancer, demethylation of survivin exon 1 by dMTase correlated positively with higher survivin levels [14]. In breast carcinoma, a significant correlation has been found between MBD2 (Methyl-CpG Binding Domain protein 2) and survivin expression [12]. However, in acute myeloid leukaemia, the methylation status is not an aggravating factor in survivin up-regulation as the survivin promoter is unmethylated in both normal and pathological cells [15]. In neuroblastoma, survivin expression correlated with survivin gene duplication. Indeed, in patients expressing high levels of survivin the survivin gene was duplicated; such patients had a poor prognosis [16]. In breast tumours, survivin expression was not influenced by the number of gene copies, but survivin overexpression correlated with microsatellite instability, especially allelic loss of D3S1478 and D6S264, both of which are close to putative tumour suppressor genes such as RASSF1 (Ras ASSociation domain Family protein 1), suggesting that genes located in these regions could control survivin expression [12]. Taken together, these results indicate that the methylation status of the survivin gene did not seem to be an
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Fig. 2 Factors inhibiting and/or activating survivin mRNA expression. a Some transcription factors can bind the survivin promoter and induce its expression. For certain proteins, some binding sites are present on the survivin promoter. b In the absence of P53, Sin-3a and HDAC, E2F-1 induces survivin expression. When P53 interacts with HDAC and Sin-3a on the survivin promoter, the expression was inhibited, even in the presence of E2F-1. c HDAC2 is able to interact with P53 and bind the survivin promoter to repress its expression. d Sp1/Sp3 proteins activate survivin mRNA expression by direct interaction with the survivin promoter. In the presence of DNMT1, Sp1/ Sp3 proteins interact with DNMT1 which methylates the survivin promoter, resulting in the inhibition of survivin expression. e In presence of Sp3 on survivin promoter, P53 could interact with HDAC1 and DNMT1 and inhibit survivin mRNA expression
important factor in survivin deregulation in cancer. More interesting is the putative involvement of RASSF1 in the regulation of the survivin gene. Indeed, this observation highlighted the fact that survivin gene regulation involves numerous proteins.
Regulation by specific transcription factors Activation by different factors (Fig. 2a)
transcription factor is induced through phosphorylation by different pathways, such as Akt, for example, in response to exposure to IGF-1 (Insulin Growth Factor 1) [17], HMGCoA reductase induction [18], or the LMP2A viral protein [19] in EBV-infected cells. Whatever the stimulus, NF-jB activation stimulates the transcription of survivin [20]. The GATA-1 transcription factor is also able to stimulate survivin promoter activity by a functional constitutive GATA-1 binding site located from -373 to -364 in the survivin promoter This allows GATA-1 to induce survivin expression [5].
Involved in both cell survival and cell proliferation Involved in cell proliferation Many transcription factors have been reported to be potential inducers of survivin expression. One of the most important is NF-jB. The DNA binding activity of this
Moreover, some transcription factors have emerged as potentially important inducers of survivin transcription.
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STAT3 (Signal Transducer and Activator of Transcription 3), for example, belongs to a family of latent cytoplasmic transcription factors. After phosphorylation, STAT3 translocates to the nucleus and regulates the transcription of survivin [21–24]. STAT3 directly binds the survivin promoter on a STAT3 response element located from -264 to -256 [25]. The Pokemon transcription factor was recently reported to induce survivin transcription by interacting with the GT-boxes of the survivin promoter [26]. The survivin promoter has two E2F binding sites and one c-myc response element. For the binding sites, cell cycle-dependent expression of survivin could be due to the binding of E2F1, E2F2 or E2F3 activators on its promoter [9]. For the response element, c-myc is recruited on the survivin promoter after treatment with growth factors, and then induces survivin expression [27]. KLF5 (Kruppel-like factor 5) is a transcription factor that regulates cell signalling related to proliferation and oncogenesis, and is able to directly or indirectly induce survivin expression. KLF5 binds the survivin promoter on three KLF5 specific sites (-202, -145 and -105), or interacts with P53 to lift the P53-mediated repression of survivin expression [28]. DEC1 (Deleted in Esophageal Cancer 1) is a transcription factor involved in different cell mechanisms such as proliferation, differentiation, lymphocyte maturation, or lipid metabolism. This protein induces survivin expression by binding the survivin promoter on two Sp1 sites located at -226 and -127 [29]. Inhibition by P53 (involved in both cell survival and proliferation) P53 was one of the first proteins described as being able to inhibit survivin mRNA expression both directly and indirectly. This protein may be an important factor in the regulation of survivin expression, as an alteration of the P53 gene correlates with survivin deregulation [30, 31]. Wildtype P53 could transcriptionally repress survivin expression by interfering with E2F1 on the survivin promoter [32]. It was also observed that the recruitment of Sin-3 (a corepressor factor) and HDAC (Histone DeACetylases) by P53 on the survivin promoter (Figs. 1, 2b) is involved in the inhibition of survivin gene transcription [31, 32]. However, other studies did not find that P53 could physically interact with the survivin promoter, and concluded that HDAC-2 was involved in an indirect repressing effect of P53 (Figs. 2c, 3) on survivin expression [33–35]. A few years ago, a study in endometrial and HCT116 cells highlighted the fact that the presence of methyl residues on the survivin promoter blocked the binding of P53 on the survivin promoter and thus induced survivin expression. Likewise, demethylation of the
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Fig. 3 Survivin transcription regulation by specific pathways. Direct regulation is symbolized by a solid line and dashed lines represent indirect regulation. An arrow signifies activation while a perpendicular line means inhibition. Coloured rectangles represent important pathways involved in survivin transcription regulation. (Color figure online)
survivin promoter enabled P53 to directly interact with the survivin promoter and thus decrease survivin transcription [36]. Factors that both inhibit and activate survivin transcription (involved in cell proliferation) As mentioned above, some proteins are able to inhibit survivin transcription whereas others activate survivin mRNA expression. A third class of transcription factors are able to inhibit or activate survivin transcription depending on the stimulus. Sp1 and Sp3 transcription factors are able to transactivate the survivin promoter [10]. DNMT1 (DNa cytosine-5-methyltransferase 1), a part of the survivin expression inhibitor complex, is able to interact with Sp1 or Sp3 on the survivin promoter to methylate it and repress survivin expression (Fig. 2d) in the presence or absence of P53. However, P53 and DNMT1 synergistically repress the survivin promoter in conjunction with Sp3 [37] (Fig. 2e). The activation of APC (Adenomatous Polyposis Coli) induces TCF-4 (T Cell Factor 4) binding on specific sites of the survivin promoter, resulting in survivin transcription inhibition [38]. Consequently, when APC is mutated, survivin expression rises due to the lack of repression [39]. Likewise, the activation of b-catenin/TCF by irradiation or Casein Kinase 2 induces strong survivin expression [40, 41]. The induction of survivin expression by the b-catenin pathway is mediated by a complex formation between CBP (Creb Binding Protein) and b-catenin/TCF. When CBP is replaced by p300 (after treatment with ICG-001) in this complex, survivin expression is repressed by the
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recruitment of Sumo-1 (Small Ubiquitin-like MOdifier) and HDAC-6 on its promoter [42]. Finally, Notch family members can inhibit or activate survivin transcription. Indeed, Notch indirectly induces survivin expression by the activation and binding of RBPJj at -355 of the survivin promoter [43], whereas Notch2 blocks survivin transcription [44]. It appears that numerous proteins are involved in the regulation of survivin gene transcription. Nevertheless, among these proteins, the majority induce overexpression of the survivin gene. Moreover, these factors that induce survivin transcriptional expression are, in most cases, the final effectors of signalling pathways. This indicates that the deregulation of signalling pathways is an essential factor in survivin overexpression in cancer cells.
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Src activates FHIT. FHIT activation inhibits Akt activity, resulting in a drop in survivin expression [56]. The FHIT gene is often altered by allelic loss or by mutations in many cancers, resulting in decreased FHIT expression or FHIT protein inactivation. Both correlated strongly with increased survivin expression in colorectal cancer [57, 58]. Inhibition of the PI3K/Akt pathway induces the activation of FKHRL1 (ForKhead Homolog Rhabdomyosarcoma Like 1), which induces the down-regulation of survivin expression [59]. Finally, in chronic myelogenous leukemia, the reciprocal chromosomal translocation (9; 22)q(34;11) creates the oncogenic kinase BCR/ABL (breakpoint cluster region/ Abelson murine leukemia viral oncogene homolog) that activates JAK2 (JAnus kinase 2) and PI3K, thus inducing c-myc and consequently survivin transcription activation [60].
Regulation by signalling pathways (Fig. 3) The mitogen-activated protein kinase (MAPK) pathway Phosphoinositide 3-kinase (PI3K)/Akt pathway The protein complex PI3K/Akt is involved in numerous signalling pathways, which indicates that it plays a central role in the cell. The activation of PI3K/Akt induces survivin expression [45] through p70S6K1 protein induction, the over-expression of which stimulates survivin expression [46]. This pathway is activated by different stimuli such as activated IGF-1 [47] or CCL2 (Chemokine Ligand 2) [48] in prostate cancer, and the stimulation of EP4 receptors by prostaglandin E2 [49]. Another example is found in breast cancer where Epidermal Growth Factor Receptors induce strong survivin expression [50] due to the binding of HIF-1a (Hypoxia Inducible Factor 1a) on the GTGC sequence located from -19 to -16 in the survivin promoter [51, 52]. In breast cancer cells, HER2 (Human Egf Receptor 2) is often over-expressed, thus inducing activation of the PI3K/Akt pathway, which increases NFjB expression and activation, followed by the induction of c-myc expression and the over-expression of survivin [53]. The PI3K/Akt pathway can also be activated after Ras isoprenylation [54]. This Ras activation is induced by farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are produced by HMG-CoA reductase during cholesterol synthesis. Moreover, HMG-CoA reductase expression correlates positively with survivin expression, suggesting that HMG-CoA reductase up-regulation induces survivin expression via the production of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, the isoprenylation of Ras, the activation of Akt and finally, the activation of NF-jB [55]. In contrast, the inhibition of PI3K/Akt down-regulates survivin expression. For example, the phosphorylation of FHIT (Fragile Histidine Triad) protein on its lysine 114 by
The MAPK pathway seems to be the second most important pathway involved in survivin transcription regulation. The treatment of breast cancer SK-BR-3 cells with EGF (Epidermal Growth Factor) induces Akt and MAPK pathway activation. In these cells, the inhibition of the MAPK pathway triggers a decrease in survivin transcription, suggesting that survivin expression could be regulated by this pathway [51]. In KBM5 cells derived from chronic myeloid leukaemia with Philadelphia chromosome, the stimulation of Bcr/Abl activates MAPK and increases survivin mRNA expression [61], partially through c-myc activation [27]. Moreover, MKK4 (MAPK Kinase 4) is required for the TNF-induced expression of survivin. Indeed, MKK4 acts as a necessary step in the NF-jB activation pathway in response to TNF and also to LPS, PMA and CSC [62]. MAPK (ERK) belongs to the Raf-1/MEK/ERK pathway and is phosphorylated by MEK, which is itself phosphorylated by Raf-1. By this mechanism, Bcl-2 mediates a signalling cascade via the Raf-MEK-ERK pathway and upregulates survivin expression [63]. Cyclooxygenase and other pathways Several studies reported a positive correlation between COX-2 (Cyclo OXygenase 2) and survivin expressions in endometrial [64], colon [65], and ovarian [66] cancers. COX-2 is able to activate b-catenin thanks to the production and binding of prostaglandin E2 on EP2 receptors [67]. Moreover, the overexpression of COX-2 increases IL-6 (Interleukin 6) expression, resulting in the phosphorylation of STAT3 and consequently the overexpression of survivin [68]. STAT3 is also induced by EML4-ALK in lung cancer and increases survivin transcription [69]. Another
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interleukin, Interleukin-4 (IL-4), induces survivin expression through the phosphorylation of STAT6 during the differentiation of colon cancer stem cells. This phenomenon is stopped in the presence of an IL-4 blocking antibody [70]. The above shows that signalling pathway deregulation is one of the most important factors of survivin overexpression in cancer. The PI3K/Akt pathway is at the origin of a large number of pathways and is stimulated by numerous membrane receptors. The targeting of the PI3K/Akt pathway by different targeted therapies (the development of which is booming) seems to be a promising strategy to selectively decrease survivin expression in cancer cells.
Therapeutic strategies targeting survivin expression Six years ago, Sepantronium bromide, known as YM155, was described as an inhibitor of survivin expression with anti-tumor activity [71], and has been tested in several clinical trials. Recently, it was reported that YM155 could act by inhibiting survivin promoter activity. It seemed that YM155 could disrupt the Sp1/DNA complex on the Survivin promoter [72]. Last year, a new inhibitor of survivin expression, NSC 80467, a fused naphthquinone imidazolium, was described and compared with YM155 [73]. It appeared that the inhibition of survivin expression by both compounds was subsequent to the activation of DNA damage response mechanisms.
Conclusion As shown in this mini-review, survivin transcription is a very complex mechanism due to the high number of parameters involved in its regulation. It is therefore difficult to know which mechanism is really responsible for survivin up-regulation in cancer. Some proteins, such as P53, PI3K/Akt and NF-jB, seem to be highly implicated in survivin transcription regulation while others appear to be more cancer tissue specific. In several clinical studies survivin expression has been diminished by using small interfering RNA or antisense RNA, but the resulting effects were not specific to cancer tissue. In cancer therapy, targeting of the specific mechanisms involved in survivin upregulation could help to make treatments more specific to cancer tissue and less toxic to normal cells, for which survivin is essential. The current development of therapies that target the over-activation of signalling pathway opens the way for new treatment strategies. Acknowledgments We thank Philip Bastable (CHU Le Bocage, Dijon, France) for editing the manuscript. RB was financially supported by the Ligue contre le Cancer de Coˆte d’Or and Ligue contre le
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Mol Biol Rep (2014) 41:233–240 Cancer de l’Yonne and FV was granted by the Ligue nationale contre le Cancer. Conflict of interest The authors have no conflict of interest to declare.
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Transcriptional regulation of the survivin gene Romain Boidot • Fre´de´rique Ve´gran Sarab Lizard-Nacol
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Received: 20 December 2012 / Accepted: 30 October 2013 / Published online: 7 November 2013 Ó Springer Science+Business Media Dordrecht 2013
Abstract Survivin, a small member of the inhibitors of the apoptosis protein family, is highly deregulated in cancer. It is weakly expressed in normal tissues but very strongly expressed in malignant lesions. Survivin is involved in cell-cycle progression, especially in the G2/M transition, and has anti-apoptotic activity, which correlates with its strong expression in cases with a poor cancer treatment response and poor outcomes. Several therapies that target the survivin transcript or protein are currently being tested in clinical trials. However, focusing new therapies on the origins of survivin overexpression and targeting these upstream deregulations could be more effective. For this reason, it seems important to make an inventory of the transcriptional (de)regulation of survivin. This review will gather the important points concerning the regulation of survivin mRNA expression: structure of the survivin promoter, epigenetic modifications and genetic abnormalities, transcription factors, and signalling pathways that affect survivin mRNA expression.
Introduction Survivin contains only one BIR (Baculovirus IAP Repeat) domain and is involved in cell-cycle progression and apoptosis inhibition. The human survivin gene, named birc5, consists of 4 exons and 3 introns spanning 14796 nt on chromosome 17q25 [1]. Its alternative transcription gives rise to five different transcripts: survivin, survivin-DEx3, survivin3B, survivin-2B and survivin-2a. Survivin is periodically expressed during the cell cycle. Its expression is weak in G1, multiplied by 6 in the S phase and by more than 40 in G2/M [2]. Survivin is weakly expressed in normal adult tissues but is highly expressed in many cancers such as breast, colon and lung cancer [1, 3]. In cancer cells, the main role of Survivin is the inhibition of apoptosis. Its overexpression greatly inhibits cell death, whereas its down-expression induces massive apoptosis in response to cytotoxic drugs.
Survivin mRNA expression in normal cells Keywords Transcription factors Genetic alterations Signalling pathways survivin gene Transcription regulation
R. Boidot (&) F. Ve´gran S. Lizard-Nacol Unit of Molecular Biology, Centre Georges-Franc¸ois Leclerc, 1, rue du Professeur Marion, 21079 Dijon Cedex, France e-mail: [email protected] F. Ve´gran Faculte´ de Me´decine, Equipe AVENIR, Inserm U866, Dijon, France
Survivin is strongly expressed in cancerous tissues but its expression is also detected in normal tissues [4, 5], especially in myeloid stem cells, umbilical cord blood CD34? cells, peripheral blood mononuclear cells and T lymphocytes [6, 7]. These last two studies highlighted the fact that survivin was expressed at all stages of the cell cycle and not only at the G2/ M transition, and that growth factor stimulation of CD34? cells induced an increase in survivin mRNA (and protein) expression. In addition, the activation of naive T lymphocytes induced increased survivin expression, which correlated with cell proliferation [6]. The same phenomena were recently observed in normal dividing cells [8]. Survivin expression is indispensable for the G2/M transition. The increase in survivin expression at this phase
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could be explained by the lifting of inhibition that occurs during the G1 and S phases. Indeed, Cyclin-Dependent Kinase 4 CDK4 is only active during the G1 and S phases. Activated CDK4 phosphorylates Rb, which binds the survivin promoter and represses its activity [9]. In G2, CDK4 is inactivated and Rb is not able to repress survivin promoter activity, thus inducing an increase in survivin expression for the G2/M transition. Over the years, the cancer specificity of survivin has been called into question. It appears that survivin is undoubtedly overexpressed in cancer tissues, where it plays a critical role in cancer progression. Nevertheless, as we have seen, its expression also seems very important in normal cells, especially for cell-cycle progression. These observations tend to indicate that the direct targeting of survivin could have dangerous side effects by also affecting normal cells. The involvement of survivin in normal cell-cycle progression indicates that the targeting of survivin should be indirect and achieved by inhibiting proteins or pathways involved in its high expression in cancer cells. Survivin promoter specificities (Fig. 1) The survivin promoter possesses a canonical CpG island and numerous Sp1 sites but no TATA box [1]. Among the numerous Sp1 sites, three are indispensable to gene transcription: -171, -151, and -140 [10]. The survivin proximal promoter also contains 3 CDE (Cell-cycle Dependent Element) at -6, -12, -171 and one CHR (Cell-cycle gene Homology Region) at -42. Both kinds of sequences are characteristic of genes expressed during G2/M and allow the periodicity of the cell cycle via an interaction with CDF-1 (Cycling DOF Factor 1), a G1 regulator protein.
Fig. 1 Proximal survivin promoter specificities. Solid red lines correspond to Sp1 sites and asterisks represent indispensable Sp1 sites for survivin expression. Solid blue lines highlight CDE regions and dashed blue line correspond to CHR sequences. Transcription factor binding sites are indicated in purple. SNP sequences are indicated with green lines. Bold arrow shows the transcription start and the ?1 points out the translation start codon. (Color figure online)
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Moreover, it has been shown that a C/G polymorphism at -31, located in the CDE/CHR repressor element, was a genetic defect found in tumour cells but not normal cell lines, and that this polymorphism correlated with increased survivin expression. This change may inhibit the binding of specific proteins on CDE elements and thus lead to the derepression of survivin transcription [11], though in breast carcinoma, this polymorphism does not influence survivin expression [12]. However, at the -235 site, a G/A sequence is strongly associated with survivin expression in breast carcinoma. The presence of an A at -235 creates a GATA-1 transcription factor binding site that induces survivin expression by the interaction between GATA-1 and the survivin promoter [5]. The specific features of the survivin promoter could explain its expression profile observed in normal cells. Indeed, specific sequences such as CDE and CHR directly influence its specific expression in G2/M. Moreover, as GATA-1 is a transcription factor expressed in red blood cell precursors and survivin is required for good erythroid differentiation [13], we can imagine that individuals with G/A may have a greater number of red blood cells than do individuals with G/G. Nevertheless, the deregulation of survivin gene expression in cancer is a consequence of different alterations, including epigenetic modifications and genetic abnormalities.
Epigenetic modifications and genetic abnormalities The survivin gene has a CpG island in exon 1 [1], which is possibly involved in the regulation of its expression. In ovarian cancer, demethylation of survivin exon 1 by dMTase correlated positively with higher survivin levels [14]. In breast carcinoma, a significant correlation has been found between MBD2 (Methyl-CpG Binding Domain protein 2) and survivin expression [12]. However, in acute myeloid leukaemia, the methylation status is not an aggravating factor in survivin up-regulation as the survivin promoter is unmethylated in both normal and pathological cells [15]. In neuroblastoma, survivin expression correlated with survivin gene duplication. Indeed, in patients expressing high levels of survivin the survivin gene was duplicated; such patients had a poor prognosis [16]. In breast tumours, survivin expression was not influenced by the number of gene copies, but survivin overexpression correlated with microsatellite instability, especially allelic loss of D3S1478 and D6S264, both of which are close to putative tumour suppressor genes such as RASSF1 (Ras ASSociation domain Family protein 1), suggesting that genes located in these regions could control survivin expression [12]. Taken together, these results indicate that the methylation status of the survivin gene did not seem to be an
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Fig. 2 Factors inhibiting and/or activating survivin mRNA expression. a Some transcription factors can bind the survivin promoter and induce its expression. For certain proteins, some binding sites are present on the survivin promoter. b In the absence of P53, Sin-3a and HDAC, E2F-1 induces survivin expression. When P53 interacts with HDAC and Sin-3a on the survivin promoter, the expression was inhibited, even in the presence of E2F-1. c HDAC2 is able to interact with P53 and bind the survivin promoter to repress its expression. d Sp1/Sp3 proteins activate survivin mRNA expression by direct interaction with the survivin promoter. In the presence of DNMT1, Sp1/ Sp3 proteins interact with DNMT1 which methylates the survivin promoter, resulting in the inhibition of survivin expression. e In presence of Sp3 on survivin promoter, P53 could interact with HDAC1 and DNMT1 and inhibit survivin mRNA expression
important factor in survivin deregulation in cancer. More interesting is the putative involvement of RASSF1 in the regulation of the survivin gene. Indeed, this observation highlighted the fact that survivin gene regulation involves numerous proteins.
Regulation by specific transcription factors Activation by different factors (Fig. 2a)
transcription factor is induced through phosphorylation by different pathways, such as Akt, for example, in response to exposure to IGF-1 (Insulin Growth Factor 1) [17], HMGCoA reductase induction [18], or the LMP2A viral protein [19] in EBV-infected cells. Whatever the stimulus, NF-jB activation stimulates the transcription of survivin [20]. The GATA-1 transcription factor is also able to stimulate survivin promoter activity by a functional constitutive GATA-1 binding site located from -373 to -364 in the survivin promoter This allows GATA-1 to induce survivin expression [5].
Involved in both cell survival and cell proliferation Involved in cell proliferation Many transcription factors have been reported to be potential inducers of survivin expression. One of the most important is NF-jB. The DNA binding activity of this
Moreover, some transcription factors have emerged as potentially important inducers of survivin transcription.
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STAT3 (Signal Transducer and Activator of Transcription 3), for example, belongs to a family of latent cytoplasmic transcription factors. After phosphorylation, STAT3 translocates to the nucleus and regulates the transcription of survivin [21–24]. STAT3 directly binds the survivin promoter on a STAT3 response element located from -264 to -256 [25]. The Pokemon transcription factor was recently reported to induce survivin transcription by interacting with the GT-boxes of the survivin promoter [26]. The survivin promoter has two E2F binding sites and one c-myc response element. For the binding sites, cell cycle-dependent expression of survivin could be due to the binding of E2F1, E2F2 or E2F3 activators on its promoter [9]. For the response element, c-myc is recruited on the survivin promoter after treatment with growth factors, and then induces survivin expression [27]. KLF5 (Kruppel-like factor 5) is a transcription factor that regulates cell signalling related to proliferation and oncogenesis, and is able to directly or indirectly induce survivin expression. KLF5 binds the survivin promoter on three KLF5 specific sites (-202, -145 and -105), or interacts with P53 to lift the P53-mediated repression of survivin expression [28]. DEC1 (Deleted in Esophageal Cancer 1) is a transcription factor involved in different cell mechanisms such as proliferation, differentiation, lymphocyte maturation, or lipid metabolism. This protein induces survivin expression by binding the survivin promoter on two Sp1 sites located at -226 and -127 [29]. Inhibition by P53 (involved in both cell survival and proliferation) P53 was one of the first proteins described as being able to inhibit survivin mRNA expression both directly and indirectly. This protein may be an important factor in the regulation of survivin expression, as an alteration of the P53 gene correlates with survivin deregulation [30, 31]. Wildtype P53 could transcriptionally repress survivin expression by interfering with E2F1 on the survivin promoter [32]. It was also observed that the recruitment of Sin-3 (a corepressor factor) and HDAC (Histone DeACetylases) by P53 on the survivin promoter (Figs. 1, 2b) is involved in the inhibition of survivin gene transcription [31, 32]. However, other studies did not find that P53 could physically interact with the survivin promoter, and concluded that HDAC-2 was involved in an indirect repressing effect of P53 (Figs. 2c, 3) on survivin expression [33–35]. A few years ago, a study in endometrial and HCT116 cells highlighted the fact that the presence of methyl residues on the survivin promoter blocked the binding of P53 on the survivin promoter and thus induced survivin expression. Likewise, demethylation of the
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Fig. 3 Survivin transcription regulation by specific pathways. Direct regulation is symbolized by a solid line and dashed lines represent indirect regulation. An arrow signifies activation while a perpendicular line means inhibition. Coloured rectangles represent important pathways involved in survivin transcription regulation. (Color figure online)
survivin promoter enabled P53 to directly interact with the survivin promoter and thus decrease survivin transcription [36]. Factors that both inhibit and activate survivin transcription (involved in cell proliferation) As mentioned above, some proteins are able to inhibit survivin transcription whereas others activate survivin mRNA expression. A third class of transcription factors are able to inhibit or activate survivin transcription depending on the stimulus. Sp1 and Sp3 transcription factors are able to transactivate the survivin promoter [10]. DNMT1 (DNa cytosine-5-methyltransferase 1), a part of the survivin expression inhibitor complex, is able to interact with Sp1 or Sp3 on the survivin promoter to methylate it and repress survivin expression (Fig. 2d) in the presence or absence of P53. However, P53 and DNMT1 synergistically repress the survivin promoter in conjunction with Sp3 [37] (Fig. 2e). The activation of APC (Adenomatous Polyposis Coli) induces TCF-4 (T Cell Factor 4) binding on specific sites of the survivin promoter, resulting in survivin transcription inhibition [38]. Consequently, when APC is mutated, survivin expression rises due to the lack of repression [39]. Likewise, the activation of b-catenin/TCF by irradiation or Casein Kinase 2 induces strong survivin expression [40, 41]. The induction of survivin expression by the b-catenin pathway is mediated by a complex formation between CBP (Creb Binding Protein) and b-catenin/TCF. When CBP is replaced by p300 (after treatment with ICG-001) in this complex, survivin expression is repressed by the
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recruitment of Sumo-1 (Small Ubiquitin-like MOdifier) and HDAC-6 on its promoter [42]. Finally, Notch family members can inhibit or activate survivin transcription. Indeed, Notch indirectly induces survivin expression by the activation and binding of RBPJj at -355 of the survivin promoter [43], whereas Notch2 blocks survivin transcription [44]. It appears that numerous proteins are involved in the regulation of survivin gene transcription. Nevertheless, among these proteins, the majority induce overexpression of the survivin gene. Moreover, these factors that induce survivin transcriptional expression are, in most cases, the final effectors of signalling pathways. This indicates that the deregulation of signalling pathways is an essential factor in survivin overexpression in cancer cells.
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Src activates FHIT. FHIT activation inhibits Akt activity, resulting in a drop in survivin expression [56]. The FHIT gene is often altered by allelic loss or by mutations in many cancers, resulting in decreased FHIT expression or FHIT protein inactivation. Both correlated strongly with increased survivin expression in colorectal cancer [57, 58]. Inhibition of the PI3K/Akt pathway induces the activation of FKHRL1 (ForKhead Homolog Rhabdomyosarcoma Like 1), which induces the down-regulation of survivin expression [59]. Finally, in chronic myelogenous leukemia, the reciprocal chromosomal translocation (9; 22)q(34;11) creates the oncogenic kinase BCR/ABL (breakpoint cluster region/ Abelson murine leukemia viral oncogene homolog) that activates JAK2 (JAnus kinase 2) and PI3K, thus inducing c-myc and consequently survivin transcription activation [60].
Regulation by signalling pathways (Fig. 3) The mitogen-activated protein kinase (MAPK) pathway Phosphoinositide 3-kinase (PI3K)/Akt pathway The protein complex PI3K/Akt is involved in numerous signalling pathways, which indicates that it plays a central role in the cell. The activation of PI3K/Akt induces survivin expression [45] through p70S6K1 protein induction, the over-expression of which stimulates survivin expression [46]. This pathway is activated by different stimuli such as activated IGF-1 [47] or CCL2 (Chemokine Ligand 2) [48] in prostate cancer, and the stimulation of EP4 receptors by prostaglandin E2 [49]. Another example is found in breast cancer where Epidermal Growth Factor Receptors induce strong survivin expression [50] due to the binding of HIF-1a (Hypoxia Inducible Factor 1a) on the GTGC sequence located from -19 to -16 in the survivin promoter [51, 52]. In breast cancer cells, HER2 (Human Egf Receptor 2) is often over-expressed, thus inducing activation of the PI3K/Akt pathway, which increases NFjB expression and activation, followed by the induction of c-myc expression and the over-expression of survivin [53]. The PI3K/Akt pathway can also be activated after Ras isoprenylation [54]. This Ras activation is induced by farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are produced by HMG-CoA reductase during cholesterol synthesis. Moreover, HMG-CoA reductase expression correlates positively with survivin expression, suggesting that HMG-CoA reductase up-regulation induces survivin expression via the production of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, the isoprenylation of Ras, the activation of Akt and finally, the activation of NF-jB [55]. In contrast, the inhibition of PI3K/Akt down-regulates survivin expression. For example, the phosphorylation of FHIT (Fragile Histidine Triad) protein on its lysine 114 by
The MAPK pathway seems to be the second most important pathway involved in survivin transcription regulation. The treatment of breast cancer SK-BR-3 cells with EGF (Epidermal Growth Factor) induces Akt and MAPK pathway activation. In these cells, the inhibition of the MAPK pathway triggers a decrease in survivin transcription, suggesting that survivin expression could be regulated by this pathway [51]. In KBM5 cells derived from chronic myeloid leukaemia with Philadelphia chromosome, the stimulation of Bcr/Abl activates MAPK and increases survivin mRNA expression [61], partially through c-myc activation [27]. Moreover, MKK4 (MAPK Kinase 4) is required for the TNF-induced expression of survivin. Indeed, MKK4 acts as a necessary step in the NF-jB activation pathway in response to TNF and also to LPS, PMA and CSC [62]. MAPK (ERK) belongs to the Raf-1/MEK/ERK pathway and is phosphorylated by MEK, which is itself phosphorylated by Raf-1. By this mechanism, Bcl-2 mediates a signalling cascade via the Raf-MEK-ERK pathway and upregulates survivin expression [63]. Cyclooxygenase and other pathways Several studies reported a positive correlation between COX-2 (Cyclo OXygenase 2) and survivin expressions in endometrial [64], colon [65], and ovarian [66] cancers. COX-2 is able to activate b-catenin thanks to the production and binding of prostaglandin E2 on EP2 receptors [67]. Moreover, the overexpression of COX-2 increases IL-6 (Interleukin 6) expression, resulting in the phosphorylation of STAT3 and consequently the overexpression of survivin [68]. STAT3 is also induced by EML4-ALK in lung cancer and increases survivin transcription [69]. Another
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interleukin, Interleukin-4 (IL-4), induces survivin expression through the phosphorylation of STAT6 during the differentiation of colon cancer stem cells. This phenomenon is stopped in the presence of an IL-4 blocking antibody [70]. The above shows that signalling pathway deregulation is one of the most important factors of survivin overexpression in cancer. The PI3K/Akt pathway is at the origin of a large number of pathways and is stimulated by numerous membrane receptors. The targeting of the PI3K/Akt pathway by different targeted therapies (the development of which is booming) seems to be a promising strategy to selectively decrease survivin expression in cancer cells.
Therapeutic strategies targeting survivin expression Six years ago, Sepantronium bromide, known as YM155, was described as an inhibitor of survivin expression with anti-tumor activity [71], and has been tested in several clinical trials. Recently, it was reported that YM155 could act by inhibiting survivin promoter activity. It seemed that YM155 could disrupt the Sp1/DNA complex on the Survivin promoter [72]. Last year, a new inhibitor of survivin expression, NSC 80467, a fused naphthquinone imidazolium, was described and compared with YM155 [73]. It appeared that the inhibition of survivin expression by both compounds was subsequent to the activation of DNA damage response mechanisms.
Conclusion As shown in this mini-review, survivin transcription is a very complex mechanism due to the high number of parameters involved in its regulation. It is therefore difficult to know which mechanism is really responsible for survivin up-regulation in cancer. Some proteins, such as P53, PI3K/Akt and NF-jB, seem to be highly implicated in survivin transcription regulation while others appear to be more cancer tissue specific. In several clinical studies survivin expression has been diminished by using small interfering RNA or antisense RNA, but the resulting effects were not specific to cancer tissue. In cancer therapy, targeting of the specific mechanisms involved in survivin upregulation could help to make treatments more specific to cancer tissue and less toxic to normal cells, for which survivin is essential. The current development of therapies that target the over-activation of signalling pathway opens the way for new treatment strategies. Acknowledgments We thank Philip Bastable (CHU Le Bocage, Dijon, France) for editing the manuscript. RB was financially supported by the Ligue contre le Cancer de Coˆte d’Or and Ligue contre le
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Mol Biol Rep (2014) 41:233–240 Cancer de l’Yonne and FV was granted by the Ligue nationale contre le Cancer. Conflict of interest The authors have no conflict of interest to declare.
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