WTAP-mediated m6A modification promotes drug sensitivity by regulating NR3C1 in prostate cancer.

The specific mechanisms of N6-methyladenosine (m6A) in castration-resistant prostate cancer (CRPC) remain incompletely understood. Wilms' tumor 1 and pyruvate kinase M2-like protein (WTAP) serve as a major regulatory factor of m6A. However, whether it regulates CRPC through m6A mechanisms is unclear. This research revealed that WTAP stands out as a key regulator among m6A factors, and considerably influences the development and behavior of CRPC. WTAP was downregulated in CRPC. A low WTAP expression predicts poor survival and a high WTAP promotes the flutamide drug sensitivity of CRPC cells. WTAP-modulated m6A modification, which can be recognized by YTHDF2, contributes to the post-transcriptional inactivation of nuclear receptor subfamily 3 group C member 1 (NR3C1). In vitro and in vivo experiments unveiled the key role of NR3C1, a rarely studied oncoprotein, in CRPC. The WTAP/YTHDF2/NR3C1 axis was actively involved in CRPC malignancy and the flutamide drug sensitivity of CRPC cells. The clinical correlation of WTAP, YTHDF2, and NR3C1 was further demonstrated in CRPC tissues and castration-dependent prostate cancer tissues. Our study uncovered a novel molecular mechanism by which the m6A-induced WTAP/YTHDF2/NR3C1 axis promotes CRPC flutamide drug sensitivity. This finding suggests the potential of WTAP as a promising prognostic marker and therapeutic target against flutamide drug sensitivity in CRPC.