Telomerase plays a key role in bypassing cellular senescence and maintaining telomere homeostasis, essential properties required for the sustenance and progression of cancer. However, recent researches have uncovered noncanonical properties of telomerase that are independent of its role in telomere extension. The following picture is the human telomerase structure model.
As we know, telomerase consists of TERT subunit, RNA subunit and a group of accessory protein , repaires chromosomal shrinkage resulting from the “end-replication” problem. It plays the critical role in maintaining the balance between normal cellular differentiation and the aberrant proliferation manifested in carcinogenic transformation.
Recently, researchers proposed a model of the feed-forward regulatory loop underscoring the interaction of TERT with the Wnt/β-catenin and NF-κB signaling pathways during cancer development. Reactivated TERT acts as a transcriptional modulator of Wnt/β-catenin and NF-κB signaling, resulting in the enhanced expression of Wnt and NF-κB target genes that exert cancer-promoting functions such as proliferation, resistance to apoptosis, and chronic inflammation. As Wnt/β-catenin and NF-κB are also transcriptional activators of TERT, the researchers suggest a feed-forward pathway (illustrated by blue arrows) that sustains Wnt/β-catenin and NF-κB–dependent transcription as well as levels of telomerase in cancer cells in a simplified schematic of signaling events.
In view of the evidence mentioned earlier linking the noncanonical functions of telomerase to cancer development and progression, targeting telomerase as an anticancer strategy seems to be an effective approach to simultaneously dampen oncogenic signaling pathways that are augmented by telomerase and disrupt the feed-forward regulatory mechanism driving chronic inflammatory/oncogenic responses and sustained telomerase activity in cancers. Furthermore, as telomerase is often upregulated in cancer cells, whereas majority of normal somatic cells have undetectable telomerase activities, telomerase-targeted cancer therapies serve to selectively eliminate tumor cells and avoid the adverse side effects. More and more evidence indicates a compelling rationale for the development of therapeutic approaches that target the noncanonical roles of telomerase, instead of solely relying on conventional small-molecule inhibitors that restrict its enzymatic activity or accessibility/function at telomeres.
Reference:
1. Noncanonical functions of telomerase: implications in telomerase-targeted cancer therapies. Cancer Res. 2014 Mar 15;74(6):1639-44.
2. Structural basis for telomerase catalytic subunit TERT binding to RNA template and telomeric DNA. Nat Struct Mol Biol. 2010 Apr;17(4):513-8
3. Human telomerase model shows the role of the TEN domain in advancing the double helix for the next polymerization step. Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9443-8
4. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature. 2009 Jul 2;460(7251):66-72.
5. Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Science. 2012 Jun 22;336(6088):1549-54.
6. Telomerase directly regulates NF-κB-dependent transcription. Nat Cell Biol. 2012 Dec;14(12):1270-81.