TROP2 translation mediated by dual m6A/m7G RNA modifications promotes bladder cancer development

Abstract

RNA modifications, including adenine methylation (m⁶A) of mRNA and guanine methylation (m⁷G) of tRNA, are crucial for the biological function of RNA. However, the mechanism underlying the translation of specific genes synergistically mediated by dual m⁶A/m⁷G RNA modifications in bladder cancer (BCa) remains unclear. We demonstrated that m⁶A methyltransferase METTL3-mediated programmable m⁶A modification of oncogene trophoblast cell surface protein 2 (TROP2) mRNA promoted its translation during malignant transformation of bladder epithelial cells. m⁷G methyltransferase METTL1 enhanced TROP2 translation by mediating m⁷G modification of certain tRNAs. TROP2 protein inhibition decreased the proliferation and invasion of BCa cells in vitro and in vivo. Moreover, synergistical knockout of METTL3/METTL1 inhibited BCa cell proliferation, migration, and invasion; however, TROP2 overexpression partially abrogated its effect. Furthermore, TROP2 expression was significantly positively correlated with the expression levels of METTL3 and METTL1 in BCa patients. Overall, our results revealed that METTL3/METTL1-mediated dual m⁶A/m⁷G RNA modifications enhanced TROP2 translation and promoted BCa development, indicating a novel RNA epigenetic mechanism in BCa.

Keywords: Bladder cancer; RNA modification; TROP2; m(6)A; m(7)G.