YTHDC2 suppresses bladder cancer by inhibiting SOX2-mediated tumor plasticity

Pluripotent cancer stem cells play a pivotal role in inducing phenotypic plasticity across various cancer types, including bladder cancer. This plasticity, crucial for cancer progression, is largely regulated by epigenetic modifications including N6-methyladenosine (m⁶A) in RNAs. However, the role of the m⁶A reader protein YTHDC2 in this process remains poorly understood. In this study, we uncovered that the depletion of YTHDC2 significantly increased the pool of bladder cancer stem cells (BCSCs), resulting in a phenotypic shift towards a more invasive subtype of bladder cancer. This shift was characterized by enhanced proliferation, migration, invasion, and self-renewal capabilities of cancer cells, highlighting YTHDC2's function as a tumor suppressor. Mechanistically, YTHDC2 recognized and bound to m⁶A-modified SOX2 mRNA, resulting in translational inhibition of SOX2. In conclusion, our study identifies YTHDC2 as a tumor suppressor in bladder cancer through inhibiting SOX2-mediated cell pluripotency and underscores the therapeutic potential of targeting the YTHDC2-SOX2 axis in bladder cancer.