School of Kinesiology, University of Michigan, Ann Arbor, Michigan, United States of America.
PLoS One. 2023 Aug 2;18(8):e0289327. doi: 10.1371/journal.pone.0289327. eCollection 2023.
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.
端粒酶活性的调节部分包括端粒酶逆转录酶（TERT）的催化亚基的选择性剪接（AS）。尽管在癌细胞和体细胞之间存在端粒酶/TERT 抑制的治疗窗口，但干细胞表达 TERT 并依赖端粒酶活性来进行细胞的生理替换。因此，确定干细胞和癌细胞中 TERT 调节的差异对于开发基于端粒酶抑制的癌症疗法以减少对干细胞的损伤至关重要。在这项研究中，我们测量了诱导多能干细胞（iPSCs）、神经祖细胞（NPCs）和非小细胞肺癌细胞（NSCLC，Calu-6 细胞）中 TERT 剪接变体的表达和端粒酶活性。我们观察到，NOVA1-PTBP1-PTBP2 轴调节 iPSCs 及其分化为 NPCs 过程中的 TERT 选择性剪接（AS）。我们还发现，调节端粒酶活性的 TERT 剪接转换是由干细胞而不是癌细胞中的不同细胞密度诱导的。最后，我们确定了调节 TERT AS 的细胞类型特异性剪接因子。总的来说，我们的发现代表了在理解干细胞和癌细胞中 TERT AS 调节方面的重要一步。
