YTHDC1 drives senescence evasion in ovarian cancer through m6A-mediated TERT stabilization.

Abstract

N6-methyladenosine (m6A) represents the most abundant internal RNA modification, and a key regulator of gene expression, yet its role in determining cell fate decisions such as senescence remains largely unexplored. Here, we identify the nuclear m6A reader YTHDC1 as a critical regulator of telomere homeostasis and senescence evasion in ovarian cancer. YTHDC1 expression was markedly elevated in advanced-stage tumors and correlated with poor patient survival. Functional investigation demonstrated that YTHDC1 ablation induced profound proliferative arrest and established a canonical senescence landscape. Mechanistic dissection revealed that YTHDC1 directly recognizes m6A-modified TERT transcripts, thereby stabilizing telomerase mRNA and maintaining telomere homeostasis. YTHDC1 knockdown triggered telomerase dysfunction and accelerated telomere shortening. Genetic restoration of TERT effectively reversed both the proliferative defects and senescence phenotypes induced by YTHDC1 deficiency. Significantly, YTHDC1-depleted senescent cells displayed enhanced sensitivity to the senolytic agent, ABT-263. Collectively, these findings uncover a previously unrecognized epitranscriptomic-telomerase axis that dictates senescence escape, establishing YTHDC1 as a central node linking RNA modification to telomere maintenance, cellular senescence, and tumor progression.