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m6A writer WTAP targets NRF2 to accelerate bladder cancer malignancy via m6A-dependent ferroptosis regulation

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Abstract

Recent evidence have indicated that ferroptosis, a novel iron-dependent form of non-apoptotic cell death, plays a critical role in human cancers. Besides, emerging literatures have revealed the ovel function of N6-methyladenosine (m6A) in bladder cancer physiological. However, the underlying mechanism of m6A on bladder cancer is still unclear. Here, present work revealed that m6A methyltransferase (‘writer’) WTAP up-regulated in bladder cancer tissue and cells, indicating the poor prognosis of bladder cancer patients. Functionally, gain/loss-of-functional experiments illustrated that WTAP promoted the viability of bladder cancer cells and inhibited the erastin-induced ferroptosis. Mechanistically, there was a remarkable m6A modification site on 3’-UTR of endogenous antioxidant factor NRF2 RNA and WTAP could install its methylation. Moreover, m6A reader YTHDF1 recognized the m6A site on NRF2 mRNA and enhanced its mRNA stability. Therefore, these findings demonstrated potential therapeutic strategyies for bladder cancer via m6A-dependent manner.

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Authors and Affiliations

  1. The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Health and Rehabilitation Science, School of Life Science and Technology, Xi’an Jiaotong University, 710049, Xi’an, Shaanxi, P. R. China

    Ke Wang & Gang Wang

  2. Department of Urology, The First People’s Hospital of Xianyang, 712000, Xianyang, Shaanxi, P. R. China

    Ke Wang, Yarong Wang, Chengxian Han, Hanxuan Chen, Liang Shi, Abudoula Reheman, Jingkai Li, Zhaomin Li & Xinxuan Yang

  3. Departartment of Urology, The Third Hospital of Xi’an, 710021, Xi’an, Shaanxi, P. R. China

    Gang Li

  4. Shenmu Hospital, 719300, Yulin, Shaanxi, P. R. China

    Wei Zhang

  5. People’s Hospital of Wuqi County, 717600, Yan’an, Shaanxi, P. R. China

    Xiaofeng Lin

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  1. Ke Wang
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  2. Gang Wang
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  3. Gang Li
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Contributions

Ke Wang, Gang Wang, Gang Li, Wei Zhang, Yarong Wang wrote the main manuscript text. Xiaofeng Lin, Chengxian Han, Hanxuan Chen, Liang Shi, Abudoula Reheman, Jingkai Li, Zhaomin, Xinxuan Yang prepared Figs. 1, 2, 3, 4, 5 and 6. All authors reviewed the manuscript.

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Correspondence to Gang Wang.

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Wang, K., Wang, G., Li, G. et al. m6A writer WTAP targets NRF2 to accelerate bladder cancer malignancy via m6A-dependent ferroptosis regulation. Apoptosis 28, 627–638 (2023). https://doi.org/10.1007/s10495-023-01817-5

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