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Abstract

In the last decade, implications of human telomerase reverse transcriptase (hTERT), a component of ribonucleoprotein telomerase in aging, senescence, and stem cell are highly evident. Besides, the activation of hTERT is also being documented several cancer types including carcinoma. The awakening of telomerase during carcinoma initiation and development is being seen with different perspectives including genetic and epigenetic tools and events. In view of several tumor progenitors genes (also referred as epigenetic mediators), telomerase is placed as key enzyme to achieve the carcinoma phenotype and sustain during the progression. It is true that swaying of telomerase in carcinoma could be facilitated with dedicated set of epigenetic modulators and modifiers players. These epigenetic alterations are heritable, potentially reversible, and seen as the epigenetic signature of carcinoma. Several papers converge to suggest that DNA methylation, histone modification, and small non-coding RNAs are the widely appreciated epigenetic changes towards hTERT modulation. In this review, we summarize the contribution of epigenetic factors in the telomerase activation and discuss potential avenues to achieve therapeutic intervention in carcinoma.

Keywords

Epigenetic regulation carcinoma therapy microRNA methylation telomerase

Introduction

Human telomerase reverse transcriptase (hTERT) is known as the catalytic component of telomerase and described as a rate limiting factor of telomerase activity.^1–8 Hitherto, overexpression of hTERT is widely documented in more than 90% of cancer types including carcinoma.^4–9 The role of telomerase in the carcinoma-sustained growth and survival is overwhelmingly suggested.^4–8 In contrast, the telomere length is highly shortened in carcinoma, which is being stably maintained by the hTERT and associated telomeric proteins.^3,10–15

In recent times, hTERT is associated to overcome cellular senescence and achieve cellular immortality in carcinoma.^{3–6,11–15} Telomeres are manifested as an end structure to safeguard the eukaryotic chromosomes.^3–5 It is widely accepted that telomere loss could be a decisive factor in several cellular defects and altered tissue homeostasis.^3–6,16 However, a paradox scene is debated that genetically as well epigenetically dictated changes in the telomere length may swing in both ways either for curbing the cancer or helping progression.^5,15,17–24 Although, there are healthy debate on the prospects of targeting telomere and telomerase as anticancer approaches, in addition looking into epigenetic regulation of hTERT is highly appreciated.

Therefore, the contribution of genetic and extra-genetic network to modulate the hTERT transcription is widely documented.^25–34 Furthermore, utilizing the higher level of telomerase by carcinoma to achieve distinctive growth and survival advantages could be possible beyond telomere length maintenance and can act as sensor, regulator and modulators.^35–43 In this review, the focus is attempted to elaborate on epigenetic regulation of hTERT in the perspectives of carcinoma progression and futuristic avenues for therapeutic intervention.

Awakening and activation of telomerase in carcinoma

Since the discovery of telomerase enzyme, convincing consensus conclude that decrease in chromosome length is associated with normal cells as the end replication problem due to almost negligible presence of telomerase.^{3–8,12–15} Nonetheless, such bottleneck in the perspectives of lack of telomerase is not faced in germ cells as well as most malignant cancers. A large number of papers describe that telomerase as ribonucleoprotein contains human telomerase RNA, human telomerase-associated protein, or dyskerin and hTERT.^{3–8,12–15} In recent times, interests are rising to dissect out the contribution of DNA methylation, histone methylation, histone acetylation, and also non-coding RNAs in the epigenetically facilitated expression of hTERT.^{25–28,31–33,44}

Telomerase activity was detected in more than 95% of advanced stage breast cancers. It was absent in 19%–32% of less advanced cancers. Since a determination of any association between telomerase activity and patient survival is not possible at the present time, it remains to be determined whether lack of telomerase activity predicts favorable outcome.^2,45,46 The expression of TERT is regulated by Wnt/β-catenin-based signaling and could be critical in human regenerative therapy and cancer.³⁶ Recently, in spite of ambiguous opinion, TERT is accepted as an appropriate factor to show the differential capability of normal and tumor cells in terms of growth and survival advantage. Numerous proto-oncogenes, tumor suppressor genes, epigenetic modulators, modifiers, and mediators are highlighted to contribute toward complexity of telomerase control, and all together such regulations are depicted as avenues for new cancer diagnostics and therapy.⁴⁷

Several review and research findings suggest that loss of telomere and simultaneously telomerase activation could be associated with an early event in human carcinogenesis and may serve as potential indications for carcinoma such as head and neck squamous cell carcinoma (HNSCC) risk and disease outcome.⁴⁸ Several findings suggest that mammalian telomeres and subtelomeres could be regions of possible epigenetic marks creating heterochromatin characteristics.¹² Accumulating evidence also point out that tumor telomere length and integrity could be modulated by the epigenetic regulation within cancerous cells.⁴⁹ In search of contribution to epigenetic modulation in TERT activation in cancer, Wang and colleagues⁵⁰ provide evidence that methylation on the TERT promoter region may be one of the reasons to drive activation in medullary thyroid carcinomas (MTCs).⁵⁰ In case of several cancers, telomerase is generally reactivated and abundant to show activity, but ambiguity persists to show that in some cases of cancers, telomere is still short.²⁸ Chromatin architecture is seen as the landscape to view the difference between normal and breast cancer tissues. Such differences could be driven by several genetic and epigenetic actors during tumorigenesis.⁵¹ Ironically in case of breast cancer cell lines, there is a substantial decrease in the telomerase length in spite of epigenetically elevated levels and activation of telomerase. Recently, Motevalli and colleagues⁵² suggest that short telomerase may be the result of epigenetic silencing of Shelterin telosomal proteins. Their findings show that Shelterin and Shelterin-associated genes can be downregulated in breast cancer cell lines possibly via epigenetic modification promoter region of POT1.

DNA methylation and telomerase expression

Appreciable attentions are being showered to investigate the epigenetic modifiers such as DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors in the direction of basic and clinical perspectives in cancer biology.⁵³ The awakening of TERT is considered as a crucial event in human carcinogenesis through the maintenance of telomeres and, interestingly, telomere-independent mechanisms. To view the transcriptional platform as a key factor in the telomerase regulation, epigenetic modulation is convincingly reported for hTERT gene expression.

As described earlier, there exists a clear role of epigenetic modulators in the telomerase expression and activity. Besides, the possible contribution of viruses such as Epstein–Barr virus (EBV) and human papillomavirus (HPV) are emerging as epigenetic mediators to modulate through cis-activation or enhance epigenetic activation of telomerase transcription.⁵⁴ Currently, wide attention has convinced us to provide importance to the involvement of CpG island methylator phenotype (CIMP)using promoter hypermethylation epigenetic tools to target multiple genes playing a role in carcinogenesis. Among the key regulatory players, telomerase is considered as critical for the development of tumorigenesis. Zhang et al.⁵⁵ remark that elevated levels of telomerase expression and activity can be mastered by CIMP activities. In support of epigenetic contribution in TERT expression, Iliopoulos and colleagues⁵⁶ show that two factors, as epigenetic mechanisms, in the form of DNA methylation and histone modifications as well as transcription factor c-myc may regulate the TERT expression and activity in hepatocellular carcinoma (HCC).

The gradual transition of human mammary epithelial cell (HMEC) from finite life span to malignantly transformed form is revealed to possess unusual DNA methylation pattern and may process a cascade of events during the early transformation process.⁵⁷ In the past year, Kumari et al.⁵⁸ provide evidence on the contribution of DNA hypermethylation in the TERT promoter region to heighten its expression and activity. Recently, Chen et al.⁵⁹ present that Grainyhead-like 2 (GRHL2) as a novel transcription factor may bind to the TERT gene promoter and thereby control its activity. Furthermore, they reveal that GRHL2 can regulate the hTERT expression through an epigenetic mechanism possibly DNA methylation.⁵⁹

Recently, Deb and Colleagues report that the antiproliferative and apoptosis-inducing effects of CDDO-Me may be associated with arresting TERT transcription repression and activity. Furthermore, their finding inclined to reveal that CDDO-Me inhibits multiple transcription factors such as Sp1, c-Myc, and nuclear factor kappa B (NF-κB) that control TERT expression positively. In addition, they also substantiate that CDDO-Me inhibited protein levels of DNMT1 and DNMT3a, which also resulted in hypomethylation of hTERT promoter.⁶⁰ Recent findings suggest that TERT promoter methylation could be implicated in esophageal squamous cell carcinoma (ESCC). Their results show that in case of ESCC, high methylation level of TERT was found.⁶¹

Histone code and telomerase expression

There is consensus that normal human cells are faced with scenario to lose telomeres after each cell division until a few short telomeres become uncapped requiring the cells to adapt to replicative aging.^3,12–15,62 In recent times, the activation of telomerase is considered as a mechanism to decelerate the genomic instability rate due to dysfunctional telomeres.^5,15,19–24 The accepted fact is that telomerase may not push through the cancer progression, it may contribute toward the sustained growth of most advanced cancers^19,20. Better prospects are viewed as precise and selective targeting of telomerase overexpression in carcinoma, but concomitantly sparing normal cell due to lack of telomerase expression.^5,24 In recent years, there is resurgence of evidence that convince about the warranted contribution of telomerase in events such as immortalization, tumorigenesis, and cancer progression.^3–9,14,15 Sufficient findings suggest that telomerase is regulated and interacted with several key processes and players inside normal and cancer cells.^3–9,14,15 Among numerous possibilities, umpteen studies point out that epigenetic hTERT core promoter region could be regulated at the level of epigenetic control. Among various epigenetic tools, the epigenetic pathways of DNA methylation and histone modifications at the core promoter region of telomerase are proposed.^{5,11,15,17–24,49,57,63,64}

Alterations of telomerase level in several carcinomas are perceived as crucial. However, involvement of epigenetic modifiers to perturb DNA methylation and chromatin structure, including changes in histone code, is noticed. Sirtuin 1 (SIRT1), a type of modifier, is described as a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase linked with numerous biological processes including carcinoma development. A finding reports that SIRT1 may induce telomerase (TERT) activation, which is regarded as a crucial step in tumorigenesis.⁶⁵ The authors suggest that abrogating the elevated level of SIRT1 in HCC could lead to substantial loss of TERT messenger RNA (mRNA) and protein expression. Furthermore, they explain that the role of SIRT1 introduces epigenetic changes in TERT via histone acetylation and methylation at the TERT promoter. Murakami and colleagues⁶⁶ support the idea of using an inhibitor such as HDAC inhibitor FR901228 to control TERT gene by inhibiting histone deacetylation. Currently, Stern and colleagues²⁴ provide evidence to support that in case of multiple cancer cell lines, mutant TERT promoters display the active chromatin with histone code as H3K4me2/3. However, the wild-type allele preserves epigenetic silencing feature as H3K27me3 mark, and mutant promoters can only be transcriptionally active.²⁴ Abnormal behavior of HDACs as a key epigenetic agent is highly noticed and may engage in provoking cancer initiation and promotion. Upregulation of HDACs drive transcriptional enhancement of hTERT leading to cancer transformation. Yang et al.⁶⁷ provide evidence on novel HDAC inhibitor AR42 ability to diminish telomerase activity by inhibiting Akt-mediated hTERT phosphorylation.

Tumor suppressor microRNAs as driver to telomerase

Several players are accountable for modulating the endogenous level of telomerase in carcinoma such as transcriptional activators and repressors, chromatin remodeling, epigenetic modulators, and regulatory small non-coding RNAs as microRNAs (miRNAs) of length 19–25 nt.^{11,15,17–20,49,57,63,68} Since the discovery of miRNAs, their implications in almost all cellular and physiological process are highly convincing.^5,21–24 Recently, new roles of these regulatory RNAs as tumor suppressor RNAs are emerging. The potential role of miRNAs as tumor suppressor agent to control the activity and expression of TERT is being investigated. Zhu et al.¹⁸ provide evidence to suggest that tumor suppressor miRNAs-512-5P may regulate the expression of telomerase in HNSCC and possibly it may block the expression of telomerase transcription and translation process. Furthermore, they conclude that miRNA-512-5P, at the elevated level, acts as tumor suppressor by downregulating telomerase in HNSCC.^18,69 In support of implications of tumor suppressor miRNAs in TERT expression, findings suggest that a decrease in miR-138 expression can facilitate, to some extent, higher hTERT protein expression in anaplastic thyroid carcinoma (ATC) and may be considered as an option to control hTERT mRNA through multiple expressions of miRNAs.⁷⁰

Altered levels of several tumor suppressors and oncogenic nature of miRNAs are connected to cancer pathophysiology. Based on miRNA profiling studies, Mitomo et al.⁷⁰ propose that decreased expression of 11 miRNAs (including miR-138) could target the hTERT in both ATC and papillary thyroid carcinoma (PTC) cell lines in comparison with the normal thyroid tissue. Additional experimental proof also supports that the expression of tumor suppressor miRNA-299-3p is downregulated in human laryngeal cancer Hep-2 cells and ectopic expression of miRNA-299-3p could control Hep-2 cell growth by repressing the 3′-untranslated region of hTERT mRNA.⁷¹

Extending the implications of miRNAs as epigenetic tools to control telomerase expression, Xu et al.⁷² reveal that the role of miRNA-34a toward the activation of TERT could be by downregulating key players Myc and FoxM1 acting as driver for telomerase reverse transcriptase (hTERT) transcription in case of human HCC. However, data that support the contribution of tumor suppressor miRNAs in TERT activation and expression are not overwhelming, but future research scope is highly warranted. Such therapeutic strategy may open up the new mode of TERT inhibition by miRNAs leading to new non-viral gene therapy. The human TERT (hTERT) gene encrypts reverse transcriptase enzyme unit of the telomerase complex ascribed to protect the chromosome termini. Besides several other epigenetic regulation of highly activated TERT in majority of cancers, microRNAs (miRNAs) are perceived as critical players for their regulation. Recently, Hrdličková et al.⁷³ report that a set of miRNAs such as let-7g*, miR-133a, miR-138-5p, miR-342-5p, miR-491-5p, and miR-541-3p may control the TERT and Wnt signaling pathway. Kasiappan and colleagues⁷⁴ reveal that 1,25-dihydroxyvitamin D3 (1,25(OH)(2)D(3)) could inhibit the TERT expression and activity by inducing the non-coding tumor suppressor miRNA-498 which is suggested as a novel approach of anticancer therapy in ovarian cancer cell line.

Epigenetic inhibitors to telomerase therapeutic quenching

Emerging views suggest that cancer progression and development are swinging balance between right or wrong epigenetic landscape. Therefore, inhibitors to bring back the aberrant epigenetic pattern are highly defensible (Figure 1).^13,38,47,75 In line of the potent epi-landscape inhibitors, dietary agents in the form of bioactive ingredients present hope for cancer prevention and therapy. In detailed findings, bioactive components can target epigenetic modifications toward tumor suppressor genes activation and blockade of tumor promoting genes such as telomerase (Figure 1).^39–43,75

Figure 1.

This diagram illustrates the schematic model of human telomerase reverse transcriptase (hTERT) deregulation driven by epigenetic actors in carcinoma model. The gradual progression of normal epithelial cells to carcinoma is depicted step wise starting from cellular senescence due to shorter telomere after each cell division, then reached to cellular crisis in the form of end replication problem and DNA damage response activation. Then, deregulation in epigenetic control and cellular signaling pathways, hTERT is aberrantly expressed to promote and facilitate carcinoma survival needs. This model also provides scope of therapeutic regimen which may be directed toward perturbed epigenetic landscape responsible for hTERT expression.

Effect of combinatorial resveratrol and pterostilbene treatment in TNBCs is reported in the perspective of nutrition/dietary mediated modulation of epigenetic landscape in cancer. The findings indicate that these two dietary plant-derived bioactive compounds efficiently diminished the level of SIRT1, a type III HDAC. Furthermore, Kala et al.⁷⁶ suggest that the consequence of downregulation of SIRT1 is also reflected at the level of decrease in telomerase activity. The avenues are discussed to harness the evidence that uncontrolled expression of telomerase serves as a key player in incessant proliferation of several carcinomas, including breast carcinoma. There are pertinent views to show the impact of epigenetic regulation of telomerase on the basic and clinical perspectives in cancer therapy. A key player as HDAC enzyme is reported to significantly modulate the epigenetically expression of telomerase and hence support the use of histone deacetylase inhibitors (HDACi) like trichostatin A (TSA) anticancer treatment.^77,78 To support the inhibitors-based cancer therapy approaches, Kretzner and colleagues⁷⁹ clearly present evidence to show that the concomitant use of MK-0457 and MK-5108 as novel aurora kinase inhibitors (AKi) and vorinostat, an HDACi, could produce a decrease in prosurvival genes Bcl-X(L) and hTERT and an increase in proapoptotic BAD and BID genes.⁷⁹ Emerging evidence supports the use of dietary components as sulforaphane (SFN), an isothiocyanate to inhibit epigenome modifier enzyme HDAC and indirectly diminishing the expression and activity of TERT in prostate cancer cell lines.⁸⁰

The use of TSA as an inhibitor of HDAC is highly cited, and further evidence support that TSA acts as agent to downregulate DNMT1 epigenetic player, which leads to demethylation of a CTCF-binding site on the hTERT promoter in case of HCT116 carcinoma. Finally, transcriptional repression of TERT is suggested to be due to the lack of CTCF-binding site on the promoter region, and such an example strengthens the regulatory role of epigenetic enzyme in telomerase expression of HCT116 cancer cell line.⁸¹ The use of drug the 5-Aza-2′-deoxycytidine (5azadC) as an inhibitor of DNMT is widely documented, and findings support that taxol can be combined with 5azadC as a better therapeutic option for glioma to possibly target the TERT expression and activity.⁸² In support of inhibitors targeted to epigenetic players as HDAC, the authors suggest the use of vorinostat (suberoylanilide hydroxamic acid), a class of HDACis capable of reducing the expression of telomerase in A549 human lung cancer cells. Evidence suggests that vorinostat can promote the demethylation of site-specific CpGs on the promoter region of hTERT by downregulating DNMTs such as DNMT1 and DNMT3b.⁸³ In recent years, Shukla and colleagues⁸⁴ show that cucurbitacin B (CuB) can dampen the activity of two epigenetic players, such as DNMTs and HDACs, precisely at a very low dose of 60 nmol/L in H1299 cells. Their study suggests that downstream effects of blocking of DNMTs and HDACs in H1299 cells may lead to downregulation of cancer-supporting genes including telomerase and could serve as an option for anticancer drugs.

There is finding of the action of 9cUAB30, a novel synthetic retinoid X receptor-selective retinoic acid (RA), in the suppression of breast carcinoma, possibly through telomerase inhibition using epigenetic modifications.⁸⁵ In one study, Berletch et al.⁸⁶ affirm that (−)-epigallocatechin-3-gallate (EGCG) could be used to promote appreciable cell death in two breast cancer cell lines MCF-7 and HL60 and may involve epigenetic regulation. During the emergence of an option to use plant-derived bioactive constituents, Li and colleagues⁸⁷ suggest that genistein, a type of flavonoid, may act as an anticancer drug by manipulating genetic and epigenetic mechanisms to control telomerase in breast benign and cancer cells.⁸⁷ Besides, another phytochemical such as EGCG is also revealed to downregulate telomerase activity in breast cancer cells and thus promote cellular apoptosis and arrest of cancer growth.^75,88

Clinical relevance of epigenetic regulation of TERT

In recent times, numerous reports are available to support several molecular inhibitors and phytochemical agents that block epigenetic modifiers such as DNMTs and HDACs, and as a consequence, the activity and expression of TERT are blocked.^{25–33,89–92} In spite of several in vitro and in vivo studies pinpointing the concomitant use of several epigenetic inhibitors and telomerase inhibitors, the success is awaited in the form of clinical trial attempts and outcomes. However, certain clinical success in the form of small-molecule inhibitor drugs targeting DNA methylation (e.g. Dacogen, Vidaza) and broad-spectrum HDAC inhibitors (e.g. Vorinostat, Romidepsin) is highlighted in cancer therapy and achieves significant improvement in survival rate.^79,83,93,94 Such observations are faced with several limitations as criteria of anticancer activity assessment as tumor volume reduction, may not be an adequate index of activity for epigenetic treatment. Observed bottleneck in the translation of existing evidence into benefit of clinical cancer patients could be explained by the fact that epigenetic phenomena is defined as a complex event employing several genetically controlled players such as TERT, DNMT, HDACs, intracellular signaling network, and extracellular signaling pathways employing umpteen agents such as small non-coding RNAs to the large protein players.^89–94 However, prospects to predict the success of such cocktail approaches combining epigenetic player inhibitors, telomerase inhibitors, and potentially other small non-coding RNA players are encouraging and promising to envision the future success at the clinical platform. Hence, passionate drivers in the field of epigenetic research represented from the basic scientists to clinical doctors are encouraged to anticipate new challenges and issues in the path of new therapeutic discovery of clinical perspectives.

Conclusion and future prospects

The deregulated activity and expression of TERT is undoubtedly regarded as one of the driving factors in cancer progression and malignancy. Plethora of emerging evidence suggests that TERT contributes toward pro-carcinoma platform utilizing several options including the suppression of DNA damage response due to shortened telomere as well as beyond telomeric facilitation by modulating cellular growth and signaling pathways. Besides the possible TERT role in carcinoma, additional factors are being highlighted related to the regulation of TERT itself through the co-ordination of several epigenetic modifiers, modulators, and mediators. Hence, appreciable surge to dissect out the possible epigenetic tools utilized by carcinoma to promote higher TERT expression and activity is reported. In the area of anticancer therapy, it looks promising to translate the epigenetic based study in telomerase and carcinoma to achieve intervention such as phytochemical-based inhibitors, precise small molecular inhibitors, and ectopic non-viral gene therapy utilizing tumor suppressor miRNAs. Therefore, the scientific pursuits in the area of TERT and its epigenetic landscape provide and promise a hope for both basic and clinical scientists in carcinoma molecular progression and therapeutic aspects.

Footnotes

Acknowledgements

The authors thank the Cancer and Translational Research Lab for the constant support and motivation and the host institute Dr. D. Y Patil Biotechnology & Bioinformatics Institute, Dr. D. Y Patil Vidyapeeth, Pune, India, for providing resources. The authors acknowledge financial support by DST-SERB, Government of India, New Delhi, India (SERB/LS-1028/2013) and DPU Pune, India (DPU/05/01/2016).

Declaration of conflicting interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors received financial support from DSTSERB, Government of India, New Delhi, India (SERB/LS-1028/2013) and DPU Pune, India (DPU/05/01/2016).

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Epigenetic perturbation driving asleep telomerase reverse transcriptase: Possible therapeutic avenues in carcinoma

Abstract

Keywords

Introduction

Awakening and activation of telomerase in carcinoma

DNA methylation and telomerase expression

Histone code and telomerase expression

Tumor suppressor microRNAs as driver to telomerase

Epigenetic inhibitors to telomerase therapeutic quenching

Clinical relevance of epigenetic regulation of TERT

Conclusion and future prospects

Footnotes

Acknowledgements

Declaration of conflicting interest

Funding

References