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

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 N 6 -methyladenosine (m 6 A) in bladder cancer physiological. However, the underlying mec...

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Published in:Apoptosis (London) 2023-04, Vol.28 (3-4), p.627-638
Main Authors: Wang, Ke, Wang, Gang, Li, Gang, Zhang, Wei, Wang, Yarong, Lin, Xiaofeng, Han, Chengxian, Chen, Hanxuan, Shi, Liang, Reheman, Abudoula, Li, Jingkai, Li, Zhaomin, Yang, Xinxuan
Format: Article
Language:English
Subjects:
3' Untranslated Regions
Apoptosis
Biochemistry
Biomedical and Life Sciences
Biomedicine
Bladder
Bladder cancer
Cancer
Cancer patients
Cancer Research
Cell Biology
Cell Cycle Proteins
Cell death
Cells
Development and progression
Ferroptosis
Ferroptosis - genetics
Gain-Loss
Humans
Lipids
Malignancy
Manufacturers
Methylation
Methyltransferase
Methyltransferases
mRNA stability
N6-methyladenosine
NF-E2-Related Factor 2 - genetics
NRF2 protein
Oncology
Prognosis
Proteins
Reagents
RNA
RNA Splicing Factors
Tumors
Urinary Bladder Neoplasms - genetics
Urology
Virology
Writers
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Summary: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 N 6 -methyladenosine (m 6 A) in bladder cancer physiological. However, the underlying mechanism of m 6 A on bladder cancer is still unclear. Here, present work revealed that m 6 A 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 m 6 A modification site on 3’-UTR of endogenous antioxidant factor NRF2 RNA and WTAP could install its methylation. Moreover, m 6 A reader YTHDF1 recognized the m 6 A site on NRF2 mRNA and enhanced its mRNA stability. Therefore, these findings demonstrated potential therapeutic strategyies for bladder cancer via m 6 A-dependent manner.
ISSN:1360-8185
1573-675X
DOI:10.1007/s10495-023-01817-5