Opinion
Telomerase: central regulator of all of the hallmarks of cancer

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Highlights

  • Non-canonical functions of telomerase components are described.

  • We describe how these functions could directly regulate all hallmarks of cancer.

  • β−Catenin/NF-κB signaling overcomes limiting levels of TERT for telomerase activity.

  • Feed forward loop between TERT and βcatenin/MYC/NFKB signaling drives oncogenesis.

The hallmarks of cancer described by Hanahan and Weinberg are properties that cancer cells must possess for successful transformation. It is believed that each of these hallmarks is independently driven. Although elongation of telomeres is thought to be the prime function of reactivated telomerase reverse transcriptase, this activity does not account for all its effects, such as increasing cell proliferation, resistance to apoptosis, and invasion. Recent studies suggest that the telomerase subunit telomerase reverse transcriptase (TERT) has novel molecular functions including transcriptional regulation and metabolic reprogramming. We summarize these functions and discuss how they could directly regulate the various hallmarks of cancer. Finally, we suggest that therapeutics targeting noncanonical telomerase functions may work better than those that target its role in telomere extension.

Section snippets

Hallmarks of cancer and telomerase function

According to the Hanahan–Weinberg model [1] there are ten properties, called the hallmarks of cancer, that cancer cells must possess for successful oncogenesis: (i) sustaining proliferative signaling; (ii) evading growth suppressors; (iii) inducing angiogenesis; (iv) resisting cell death; (v) activating invasion and metastasis; (vi) tumor-promoting inflammation; (vii) evading immune destruction; (viii) reprogramming energy metabolism; (ix) genome instability; and (x) enabling replicative

First evidence for telomere independent roles of telomerase components

Some of the earliest evidence for telomere-independent roles of telomerase came from mouse studies. Mice have very long telomeres (20–50 kb) compared to humans (5–10 kb), therefore, there is no need for telomerase upregulation in murine tumors to prevent telomere erosion and replicative senescence. However, it has been found that TERT is upregulated in breast [18] and skin [19] cancers in mice, suggesting that TERT could play other roles besides maintaining telomere length. Supporting this idea,

Telomerase and transcriptional regulation

One of the noncanonical roles of TERT is in regulation of transcription. Artandi and colleagues reported that telomerase could regulate the transcription of genes involved in cell proliferation, glycolysis, and resistance to apoptosis [30]. Park et al. [31] then uncovered a mechanistic link between TERT and transcription, reporting that TERT associates with the chromatin remodeler, brahma related gene (BRG)1, and that this complex activates promoters of Wnt/β-catenin target genes such as Myc

Regulation of cell growth and proliferation

Expression of TERT in some human and murine cell types can cause rapid cell proliferation, which occurs without measurable changes in telomere elongation 22, 30, 34, 35. It has been found that human fibroblasts immortalized by overexpression of TERT secrete epiregulin, a growth factor belonging to the epidermal growth factor (EGF) family. Importantly, epiregulin neutralization reduces growth of these cells [36]. Although it was not directly tested, NF-κB target genes such as IL-1β and TNF-α

Therapeutic targeting of telomerase

The preceding sections have summarized how telomerase regulates the various hallmarks of cancer; that is, mainly through TERT acting as a cofactor to regulate NF-κB and β-catenin signaling pathways. These findings have therapeutic implications for the design of inhibitors that can target human ailments such as cancers, which show reactivation of TERT. For this we would need to delineate which noncanonical activities of telomerase require which components of the telomerase complex besides TERT.

Concluding remarks

In this review, we have summarized the existing literature that suggests how telomerase in general and its TERT subunit in particular can regulate the various hallmarks of cancer. We suggest that co-regulation of NF-κB and β-catenin signaling pathways by TERT could be the key mechanistic basis for the noncanonical functions of TERT, which impart its ability to regulate the hallmarks of cancer. It is important to note that the regulation of the various hallmarks of cancer by TERT should not be

Acknowledgments

The VT laboratory is funded by a core grant from A*STAR to IMCB, Singapore. KCL is supported by an A*STAR scholarship.

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