5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs

• Published in: Nature cell biology Vol. 21; no. 8; pp. 978 - 990
• Main Authors: Chen, Xin, Li, Ang, Sun, Bao-Fa, Yang, Ying, Han, Ya-Nan, Yuan, Xun, Chen, Ri-Xin, Wei, Wen-Su, Liu, Yanchao, Gao, Chun-Chun, Chen, Yu-Sheng, Zhang, Mengmeng, Ma, Xiao-Dan, Liu, Zhuo-Wei, Luo, Jun-Hang, Lyu, Cong, Wang, Hai-Lin, Ma, Jinbiao, Zhao, Yong-Liang, Zhou, Fang-Jian, Huang, Ying, Xie, Dan, Yang, Yun-Gui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2019; Nature Publishing Group
• Subjects: 101/58; 42/70; 42/89; 45/90; 45/91; 5-Methylcytosine - metabolism; 631/337/1645/2020; 631/337/1645/2570; 631/67; 64/60; 82/1; 82/83; Animals; Biomedical and Life Sciences; Bladder; Bladder cancer; Cancer; Cancer Research; Carcinoma, Transitional Cell - genetics; Carcinoma, Transitional Cell - metabolism; Cell Biology; Cold shock; Cytosine; Development and progression; Developmental Biology; Gene Expression Regulation - genetics; Genetic aspects; Health aspects; Humans; Indoles; Life Sciences; Messenger RNA; Methylation; Methyltransferases - genetics; Mice; mRNA stability; Nucleotides; Pathogenesis; Physiological aspects; RNA, Messenger - genetics; Stem Cells; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; Urothelial carcinoma; Y-Box-Binding Protein 1 - genetics; China
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/s41556-019-0361-y

Although 5-methylcytosine (m 5 C) is a widespread modification in RNAs, its regulation and biological role in pathological conditions (such as cancer) remain unknown. Here, we provide the single-nucleotide resolution landscape of messenger RNA m 5 C modifications in human urothelial carcinoma of the bladder (UCB). We identify numerous oncogene RNAs with hypermethylated m 5 C sites causally linked to their upregulation in UCBs and further demonstrate YBX1 as an m 5 C ‘reader’ recognizing m 5 C-modified mRNAs through the indole ring of W65 in its cold-shock domain. YBX1 maintains the stability of its target mRNA by recruiting ELAVL1. Moreover, NSUN2 and YBX1 are demonstrated to drive UCB pathogenesis by targeting the m 5 C methylation site in the HDGF 3′ untranslated region. Clinically, a high coexpression of NUSN2, YBX1 and HDGF predicts the poorest survival. Our findings reveal an unprecedented mechanism of RNA m 5 C-regulated oncogene activation, providing a potential therapeutic strategy for UCB. Chen et al. provide an m 5 C landscape in bladder cancer and show m 5 C enrichment at oncogene mRNAs that promotes tumour progression. They identify YBX1 as the m 5 C ‘reader’ that recruits ELAVL1 to stabilize mRNAs.