Dynamics of TERT regulation via alternative splicing in stem cells and cancer cells

Abstract

Part of the regulation of telomerase activity includes the alternative splicing (AS) of the catalytic subunit telomerase reverse transcriptase (TERT). Although a therapeutic window for telomerase/TERT inhibition exists between cancer cells and somatic cells, stem cells express TERT and rely on telomerase activity for physiological replacement of cells. Therefore, identifying differences in TERT regulation between stem cells and cancer cells is essential for developing telomerase inhibition-based cancer therapies that reduce damage to stem cells. In this study, we measured TERT splice variant expression and telomerase activity in induced pluripotent stem cells (iPSCs), neural progenitor cells (NPCs), and non-small cell lung cancer cells (NSCLC, Calu-6 cells). We observed that a NOVA1-PTBP1-PTBP2 axis regulates TERT alternative splicing (AS) in iPSCs and their differentiation into NPCs. We also found that splice-switching of TERT, which regulates telomerase activity, is induced by different cell densities in stem cells but not cancer cells. Lastly, we identified cell type-specific splicing factors that regulate TERT AS. Overall, our findings represent an important step forward in understanding the regulation of TERT AS in stem cells and cancer cells.

Genetically predicted telomere length and the risk of 11 hematological diseases: a Mendelian randomization study

“…Several studies have also explored the possibility of targeting TL for therapeutic purposes. For instance, interfering with telomerase activity inhibited AML cell proliferation and viability [ 29 ]. Further elucidation of the regulatory mechanisms of TL and AML, as well as the development of therapeutic strategies targeting TL, could facilitate early prevention and diagnosis of AML, ultimately improving patient prognosis and survival rates.…”