5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs

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.