5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs

Nat Cell Biol. 2019 Aug;21(8):978-990. doi: 10.1038/s41556-019-0361-y.

Xin Chen ¹ ², Ang Li ³ ⁴, Bao-Fa Sun ³ ⁴ ⁵, Ying Yang ³ ⁴ ⁵, Ya-Nan Han ³ ⁴, Xun Yuan ⁶, Ri-Xin Chen ¹, Wen-Su Wei ¹ ², Yanchao Liu ⁶, Chun-Chun Gao ³ ⁴, Yu-Sheng Chen ³ ⁴, Mengmeng Zhang ⁷, Xiao-Dan Ma ¹, Zhuo-Wei Liu ¹ ², Jun-Hang Luo ¹, Cong Lyu ⁴ ⁸, Hai-Lin Wang ⁴ ⁸, Jinbiao Ma ⁷, Yong-Liang Zhao ³ ⁴ ⁵, Fang-Jian Zhou ¹ ², Ying Huang ⁹, Dan Xie ¹⁰, Yun-Gui Yang ¹¹ ¹² ¹³

Affiliations

1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
2 Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China.
3 CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
4 University of Chinese Academy of Sciences, Beijing, China.
5 Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
6 State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
7 State Key Laboratory of Genetic Engineering, Collaborative Innovation Centre of Genetics and Development, Multiscale Research Institute for Complex Systems, Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai, China.
8 State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China.
9 State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. [email protected].
10 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
11 CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. [email protected].
12 University of Chinese Academy of Sciences, Beijing, China. [email protected].
13 Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China. [email protected].

PMID: 31358969 DOI: 10.1038/s41556-019-0361-y

Abstract

Although 5-methylcytosine (m⁵C) 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 m⁵C modifications in human urothelial carcinoma of the bladder (UCB). We identify numerous oncogene RNAs with hypermethylated m⁵C sites causally linked to their upregulation in UCBs and further demonstrate YBX1 as an m⁵C 'reader' recognizing m⁵C-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 m⁵C 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 m⁵C-regulated oncogene activation, providing a potential therapeutic strategy for UCB.

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