Wang Huifeng, Zhang Die, Ouyang Yiqiang, Li Jinwan, Pang Guangfu, Xie Xing, Huang Hongli, Yan Tengyue, Pang Xianwu, Zhou Qingniao, Xie Bo, Wang Fubo, An Sanqi, Hu Yanling
Department of Human Anatomy, School of Basic Medical Sciences, Guangxi Medical University, Nanning, 530021, China.
Key Laboratory of Human Development and Disease Research, Education Department of Guangxi Zhuang Autonomous Region, Guangxi Medical University, Nanning, 530021, China.
Sci China Life Sci. 2025 Jul 8. doi: 10.1007/s11427-024-2776-3.
The specific mechanisms of N-methyladenosine (mA) 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 mA. However, whether it regulates CRPC through mA mechanisms is unclear. This research revealed that WTAP stands out as a key regulator among mA 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 mA 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 mA-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.
N-甲基腺苷（mA）在去势抵抗性前列腺癌（CRPC）中的具体机制仍未完全明确。威尔姆斯瘤1和丙酮酸激酶M2样蛋白（WTAP）是mA的主要调节因子。然而，其是否通过mA机制调节CRPC尚不清楚。本研究表明，WTAP在mA相关因子中是关键调节因子，对CRPC的发生发展及生物学行为有显著影响。WTAP在CRPC中表达下调。低水平的WTAP表达预示着较差的生存率，而高水平的WTAP则可提高CRPC细胞对氟他胺的药物敏感性。WTAP介导的mA修饰可被YTHDF2识别，进而导致核受体亚家族3 C组成员1（NR3C1）的转录后失活。体外和体内实验揭示了此前研究较少的癌蛋白NR3C1在CRPC中的关键作用。WTAP/YTHDF2/NR3C1轴积极参与CRPC的恶性进展及CRPC细胞对氟他胺的药物敏感性。WTAP、YTHDF2和NR3C1之间的临床相关性在CRPC组织和去势依赖性前列腺癌组织中得到进一步证实。我们的研究发现了一种新的分子机制，即mA诱导的WTAP/YTHDF2/NR3C1轴可提高CRPC对氟他胺的药物敏感性。这一发现提示WTAP有望成为CRPC中一个有前景的预后标志物及针对氟他胺药物敏感性的治疗靶点。
