Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Nov;68(11):3151-3166.
doi: 10.1007/s11427-024-2776-3. Epub 2025 Jul 8.

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

Huifeng Wang #  1   2 , Die Zhang #  3 , Yiqiang Ouyang #  4 , Jinwan Li #  5 , Guangfu Pang #  6 , Xing Xie  7 , Hongli Huang  7 , Tengyue Yan  3 , Xianwu Pang  3 , Qingniao Zhou  8 , Bo Xie  7 , Fubo Wang  9 , Sanqi An  10 , Yanling Hu  11   12
Affiliations

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

Huifeng Wang et al. Sci China Life Sci. 2025 Nov.

Abstract

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.

Keywords: NR3C1; WTAP; YTHDF2; CRPC; drug sensitivity; m6A.

PubMed Disclaimer

Conflict of interest statement

Compliance and ethics. The authors declare that they have no conflict of interest. Ethical approval was granted by the Guangxi Medical University Institutional Animal Care and Use Committee. Animal care and experiments were conducted in compliance with the Institutional Animal Care and Use Committee and NIH guidelines. The research involving human biomedicine was reviewed and approved by the Medical Ethics Committee of Guangxi Medical University and considered to meet the requirements of medical ethics.

References

    1. An, S., Huang, W., Huang, X., Cun, Y., Cheng, W., Sun, X., Ren, Z., Chen, Y., Chen, W., and Wang, J. (2020). Integrative network analysis identifies cell-specific trans regulators of m6A. Nucleic Acids Res 48, 1715–1729. - PubMed - PMC - DOI
    1. Blomme, A., Peter, C., Mui, E., Rodriguez Blanco, G., An, N., Mason, L.M., Jamieson, L. E., McGregor, G.H., Lilla, S., Ntala, C., et al. (2022). THEM6-mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer. EMBO Mol Med 14, e14764. - PubMed - PMC - DOI
    1. Cao, J., Wei, J., Yang, P., Zhang, T., Chen, Z., He, F., Wei, F., Chen, H., Hu, H., Zhong, J., et al. (2018). Genome-scale CRISPR-Cas9 knockout screening in gastrointestinal stromal tumor with Imatinib resistance. Mol Cancer 17, 121. - PubMed - PMC - DOI
    1. Chen, K., Liu, W., Zhu, J., Kou, X., Zhao, Y., Wang, H., Jiang, C., Gao, S., and Kang, L. (2024). Pivotal role for long noncoding RNAs in zygotic genome activation in mice. Sci China Life Sci 67, 958–969. - PubMed - DOI
    1. Chen, Y., Pan, C., Wang, X., Xu, D., Ma, Y., Hu, J., Chen, P., Xiang, Z., Rao, Q., and Han, X. (2021). Silencing of METTL3 effectively hinders invasion and metastasis of prostate cancer cells. Theranostics 11, 7640–7657. - PubMed - PMC - DOI

MeSH terms

LinkOut - more resources