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

doi:10.1007/s11427-024-2776-3

. 2025 Jul 8.

doi: 10.1007/s11427-024-2776-3. Online ahead of print.

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 Xie⁷, Hongli Huang⁷, Tengyue Yan³, Xianwu Pang³, Qingniao Zhou⁸, Bo Xie⁷, Fubo Wang⁹, Sanqi An¹⁰, Yanling Hu^{11

12}

Affiliations

¹ Department of Human Anatomy, School of Basic Medical Sciences, Guangxi Medical University, Nanning, 530021, China.
² Key Laboratory of Human Development and Disease Research, Education Department of Guangxi Zhuang Autonomous Region, Guangxi Medical University, Nanning, 530021, China.
³ Collaborative Innovation Centre of Regenerative Medicine and Medical Bio Resource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning, 530021, China.
⁴ Laboratory Animal Center, Guangxi Medical University, Nanning, 530021, China.
⁵ Department of Immunology, Basic Medical College of Guangxi Medical University, Nanning, 530021, China.
⁶ Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, 530021, China.
⁷ Institute of Life Sciences, Guangxi Medical University, Nanning, 530021, China.
⁸ Department of Biochemistry and Molecular Biology, School of Pre-Clinical Medicine, Guangxi Medical University, Nanning, 530021, China.
⁹ Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, 530021, China. wangbofengye@163.com.
¹⁰ Institute of Life Sciences, Guangxi Medical University, Nanning, 530021, China. ansq@mail2.sysu.edu.cn.
¹¹ Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, 530021, China. huyanling@gxmu.edu.cn.
¹² Institute of Life Sciences, Guangxi Medical University, Nanning, 530021, China. huyanling@gxmu.edu.cn.

^# Contributed equally.

PMID: 40650812
DOI: 10.1007/s11427-024-2776-3

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

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

. 2025 Jul 8.

doi: 10.1007/s11427-024-2776-3. Online ahead of print.

Authors

Affiliations

¹ Department of Human Anatomy, School of Basic Medical Sciences, Guangxi Medical University, Nanning, 530021, China.
² Key Laboratory of Human Development and Disease Research, Education Department of Guangxi Zhuang Autonomous Region, Guangxi Medical University, Nanning, 530021, China.
³ Collaborative Innovation Centre of Regenerative Medicine and Medical Bio Resource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning, 530021, China.
⁴ Laboratory Animal Center, Guangxi Medical University, Nanning, 530021, China.
⁵ Department of Immunology, Basic Medical College of Guangxi Medical University, Nanning, 530021, China.
⁶ Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, 530021, China.
⁷ Institute of Life Sciences, Guangxi Medical University, Nanning, 530021, China.
⁸ Department of Biochemistry and Molecular Biology, School of Pre-Clinical Medicine, Guangxi Medical University, Nanning, 530021, China.
⁹ Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, 530021, China. wangbofengye@163.com.
¹⁰ Institute of Life Sciences, Guangxi Medical University, Nanning, 530021, China. ansq@mail2.sysu.edu.cn.
¹¹ Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, 530021, China. huyanling@gxmu.edu.cn.
¹² Institute of Life Sciences, Guangxi Medical University, Nanning, 530021, China. huyanling@gxmu.edu.cn.

^# Contributed equally.

PMID: 40650812
DOI: 10.1007/s11427-024-2776-3

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.

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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
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
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
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
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

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[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

[2] 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

[3] 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

[4] 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

[5] 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

[6] 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

[7] 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

[8] 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

[9] 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

[10] 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

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

Affiliations

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

Authors

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Abstract

Conflict of interest statement

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Abstract

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