The RNA-stability-independent role of the RNA m6A reader YTHDF2 in promoting protein translation to confer tumor chemotherapy resistance

Abstract

N⁶-methyladenosine (m⁶A) modification plays pivotal roles in myriad biological processes. The YTH domain family protein YTHDF2, recognized as an m⁶A "reader" protein, is primarily associated with the canonical function of facilitating RNA degradation. Nevertheless, the intricate non-decay regulatory mechanism exerted by YTHDF2 remains enigmatic. Here, using ovarian cancer as a model, we demonstrate that YTHDF2 forms a tangible interaction with the eukaryotic translation initiation factor eIF3F and the RNA helicase DDX1, thereby enhancing protein synthesis in tumor cells. Instead of promoting RNA degradation, YTHDF2 facilitates the translation of m⁶A-modified mRNAs encoding microtubule-associated proteins, which drives cancer progression and reduces the chemosensitivity of cancer cells to paclitaxel, a commonly used chemotherapy drug. Notably, through virtual screening, we identified a YTHDF2-specific small-molecule inhibitor. Therapeutic targeting of YTHDF2 with this inhibitor effectively suppresses protein translation in tumor cells and reverses paclitaxel resistance.

Keywords: YTHDF2; m(6)A; translational regulation; tumor resistance.