Crossroads of telomere biology and anticancer drug discovery

Abstract

The telomere is the specialized nucleoprotein complex at the end of the chromosome. Its highly conserved 5′‐TTAGGG‐3′ repeats and shelterin protein complexes form a protective loop structure to maintain the integrity and stability of linear chromosomes. Although human somatic cells gradually shorten telomeres to undergo senescence or crisis, cancer cells activate telomerase, or the recombination‐based mechanism to maintain telomeres and exhibit immortality. As the most frequent non‐coding mutations in cancer, gain‐of‐function mutations in the promoter region of the telomerase catalytic subunit, TERT, trigger telomerase activation. Promoter methylation and copy number gain are also associated with the enhanced TERT expression. Although telomerase inhibitors were pioneered from telomere‐directed therapeutics, their efficacies are limited to cancer with short telomeres and some hematological malignancies. Other therapeutic approaches include a nucleoside analog incorporated to telomeres and TERT promoter‐driven oncolytic adenoviruses. Tankyrase poly(ADP‐ribose) polymerase, a positive regulator of telomerase, has been rediscovered as a target for Wnt‐driven cancer. Meanwhile, telomeric nucleic acids form a higher‐order structure called a G‐quadruplex (G4). G4s are formed genome‐wide and their dynamics affect various events, including replication, transcription, and translation. G4‐stabilizing compounds (G4 ligands) exert anticancer effects and are in clinical investigations. Collectively, telomere biology has provided clues for deeper understanding of cancer, which expands opportunities to discover innovative anticancer drugs.

Oncolytic virotherapy with human telomerase reverse transcriptase promoter regulation enhances cytotoxic effects against gastric cancer

“…Therefore, we hypothesized that the antitumor effects can be enhanced by regulating the expression of ICP6, a gene crucial for viral replication, with a tumor-specific promoter such as the human telomerase reverse transcriptase (hTERT) promoter, which has demonstrated promising results (20,21) since telomeres play an important role in maintaining cellular homeostasis and senescence (22,23). As DNA polymerase fails to fully synthesize DNA termini, human telomeres in somatic cells undergo progressive shortening with cell division (24).…”

The role of the size in thyroid cancer risk stratification

“…Imetelstat 62 ), drugs inducing telomere dysfunction (e.g. 6-thio-2′-deoxyguanosine 63 ), and adenoviral gene therapies that induce telomerase promoter-driven oncolytic activity 64 are currently under investigation as potential anticancer agents. Based on the latest literature (as confirmed by the present study), telomerase could be a promising therapeutic target for RAI-refractory thyroid cancer, but no data are available as yet.…”

The PARP Enzyme Family and the Hallmarks of Cancer Part 1. Cell Intrinsic Hallmarks

“…Although telomerase activity is virtually absent from normal human nonstem adult somatic cells, in cancer, activating mutations in the promoter region, promoter methylation, and gene copy number amplification of human telomerase reverse transcriptase (hTERT), the catalytic subunits of telomerase are among the most frequent genetic/epigenetic alterations [ 99 ]. In addition, 5–15% of cancers express undetectable levels of hTERT and instead regenerate their telomeres via a recombination-directed mechanism called the alternative lengthening of telomeres (ALT) [ 100 , 101 ].…”