Trends in Biochemical Sciences
OpinionTelomerase: central regulator of all of the hallmarks of cancer
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.
References (100)
- et al.
Hallmarks of cancer: the next generation
Cell
(2011) The limited in vitro lifetime of human diploid cell strains
Exp. Cell Res.
(1965)- et al.
A survey of telomerase activity in human cancer
Eur. J. Cancer
(1997) Identification of ATPases pontin and reptin as telomerase components essential for holoenzyme assembly
Cell
(2008)NF-kappa B regulates transcription of the mouse telomerase catalytic subunit
J. Biol. Chem.
(2000)Human telomerase reverse transcriptase (hTERT) is a novel target of the Wnt/beta-catenin pathway in human cancer
J. Biol. Chem.
(2012)- et al.
Telomere dynamics and telomerase activity in in vitro immortalised human cells
Eur. J. Cancer
(1997) - et al.
The hallmarks of cancer
Cell
(2000) - et al.
Lessons from hereditary colorectal cancer
Cell
(1996) - et al.
The interplay between Mad and Myc in proliferation and differentiation
Trends Cell Biol.
(2001)
IFN-gamma/IRF-1-induced p27kip1 down-regulates telomerase activity and human telomerase reverse transcriptase expression in human cervical cancer
FEBS Lett.
Telomerase reverse transcriptase activates the expression of vascular endothelial growth factor independent of telomerase activity
Biochem. Biophys. Res. Commun.
Telomerase mediates vascular endothelial growth factor-dependent responsiveness in a rat model of hind limb ischemia
J. Biol. Chem.
VEGF- and LPA-induced telomerase in human ovarian cancer cells is Sp1-dependent
Gynecol. Oncol.
IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer
Cancer Cell
DNA damage-mediated induction of a chemoresistant niche
Cell
The depletion of interleukin-8 causes cell cycle arrest and increases the efficacy of docetaxel in breast cancer cells
Biochem. Biophys. Res. Commun.
Cancer-related inflammation: common themes and therapeutic opportunities
Semin. Cancer Biol.
New insights into chronic inflammation-induced immunosuppression
Semin. Cancer Biol.
Chronic inflammation, immunosuppression and cancer: new insights and outlook
Semin. Cancer Biol.
Myeloid differentiation factor 88-independent Toll-like receptor pathway: Sustaining inflammation or promoting tolerance?
Int. J. Biochem. Cell Biol.
IL-6 and APPs: anti-inflammatory and immunosuppressive mediators
Immunol. Today
Mechanism of human telomerase inhibition by BIBR1532, a synthetic, non-nucleosidic drug candidate
J. Biol. Chem.
Is telomerase a viable target in cancer?
Mutat. Res.
Cellular and gene expression responses involved in the rapid growth inhibition of human cancer cells by RNA interference-mediated depletion of telomerase RNA
J. Biol. Chem.
Telomeres shorten during ageing of human fibroblasts
Nature
Replication and protection of telomeres
Nature
Shelterin: the protein complex that shapes and safeguards human telomeres
Genes Dev.
The end of the (DNA) line
Nat. Struct. Biol.
Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita
Proc. Natl. Acad. Sci. U.S.A.
Telomerase activity in human germline and embryonic tissues and cells
Dev. Genet.
Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation
Oncogene
Telomerase activation in atherosclerosis and induction of telomerase reverse transcriptase expression by inflammatory stimuli in macrophages
Arterioscler. Thromb. Vasc. Biol.
A telomerase component is defective in the human disease dyskeratosis congenita
Nature
Reversible cell-cycle entry in adult kidney podocytes through regulated control of telomerase and Wnt signaling
Nat. Med.
Telomerase directly regulates NF-kappaB-dependent transcription
Nat. Cell Biol.
Telomerase activation in mouse mammary tumors: lack of detectable telomere shortening and evidence for regulation of telomerase RNA with cell proliferation
Mol. Cell. Biol.
Increased telomerase activity in mouse skin premalignant progression
Cancer Res.
Constitutive telomerase expression promotes mammary carcinomas in aging mice
Proc. Natl. Acad. Sci. U.S.A.
Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes
EMBO J.
Conditional telomerase induction causes proliferation of hair follicle stem cells
Nature
Constitutive expression of tert in thymocytes leads to increased incidence and dissemination of T-cell lymphoma in Lck-Tert mice
Mol. Cell. Biol.
Telomerase contributes to tumorigenesis by a telomere length-independent mechanism
Proc. Natl. Acad. Sci. U.S.A.
Rapid inhibition of cancer cell growth induced by lentiviral delivery and expression of mutant-template telomerase RNA and anti-telomerase short-interfering RNA
Cancer Res.
An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA
Nature
Novel dyskerin-mediated mechanism of p53 inactivation through defective mRNA translation
Cancer Res.
Pontin and reptin, two related ATPases with multiple roles in cancer
Cancer Res.
TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program
PLoS Genet.
Telomerase modulates Wnt signalling by association with target gene chromatin
Nature
Notch and NFkappaB signaling pathways: Do they collaborate in normal vertebrate brain development and function?
Bioessays
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