YTHDC1 orchestrates oncogenic splicing via the CLK1-SRSF1 splicing machinery to regulate castration-resistant prostate cancer progression.

Abstract

Androgen receptor variant 7 (AR-V7) plays a critical role in castration-resistant prostate cancer (CRPC) progression even under androgen-deprivation conditions. Clinical and experimental studies have established that AR-V7 expression is a critical driver of CRPC progression and resistance to first-line anti-androgen therapy including enzalutamide. Understanding the mechanisms regulating AR-V7 generation and its contribution to drug resistance is critical for developing newer approaches to target CRPC. In this study, we have investigated the role of the RNA-binding protein YTHDC1, a m6A reader, in regulating AR-V7 splicing. Our findings reveal that YTHDC1 is overexpressed in CRPC and modulating its expression directly affects AR-V7 levels, rendering the cells sensitive to enzalutamide treatment. Mechanistically, we demonstrate that YTHDC1 binds to the AR-V7 pre-mRNA and facilitates the recruitment of phosphorylated SRSF1, a splice factor that promotes AR-V7 splicing. Additionally, we also demonstrate that it modulates the levels of CLK1, a known SRSF1 kinase supporting its role in regulating AR-V7 splicing. Furthermore, our experiments also reveal that YTHDC1 regulates the expression of other oncogenic transcripts, including Bcl-2, Cyclin D1, Nova1, and VEGF-A, highlighting its broader role in cancer progression. Overall, our study supports that targeting YTHDC1 could be a novel therapeutic approach to overcome AR-V7-mediated treatment resistance in CRPC patients.