Revisiting Telomere Shortening in Cancer

Abstract

Telomeres, the protective structures of chromosome ends are gradually shortened by each cell division, eventually leading to senescence or apoptosis. Cancer cells maintain the telomere length for unlimited growth by telomerase reactivation or a recombination-based mechanism. Recent genome-wide analyses have unveiled genetic and epigenetic alterations of the telomere maintenance machinery in cancer. While telomerase inhibition reveals that longer telomeres are more advantageous for cell survival, cancer cells often have paradoxically shorter telomeres compared with those found in the normal tissues. In this review, we summarize the latest knowledge about telomere length alterations in cancer and revisit its rationality. Finally, we discuss the potential utility of telomere length as a prognostic biomarker.

Keywords: TERRA; TERT; biomarker; cancer; interferon stimulated gene; shelterin; telomerase; telomere; telomere position effect.

Figure 1

Bimodal implication of telomere shortening in cancer development; (A) human somatic cells shorten their telomeres at each cell cycle. Activation of oncogenes and inactivation of tumor suppressor genes lead to dysregulated cell proliferation, which further enhances telomere shortening. A critically shortened telomere causes senescence or crisis of a cell, whereas telomere reverse transcriptase (TERT) expression mainly via promoter mutation (C228T or C250T) results in telomerase activation and tumor formation; (B) in the initial step of carcinogenesis, the level of telomerase activity (TA) is insufficient to prevent telomere shortening (TS) and indicates as “TA < TS”. Under these conditions, telomerase preferentially elongates the shortest telomeres, but the level of the enzyme activity is insufficient to maintain the bulk telomere length. After several cell cycles, additional factors upregulate telomerase activity, and the bulk telomere length is maintained short in an equilibration between TA and TS (“TA = TS”). In a tumor mass, cancer cells with short telomeres upregulate interferon-stimulated genes (ISGs), which presumably contribute to the tumor malignancy. Furthermore, shortened telomeres facilitate cancer evolution by causing moderate chromosomal instability; (C) in experimental settings, ectopic overexpression of TERT induces telomere elongation in cancer cells, which is followed by TERRA upregulation and repression of ISG expression. Because TERRA-like oligonucleotides repress ISG induction, shortened telomeres, which provide reduced TERRA levels, may be more advantageous for cancer.