A novel tsRNA, m7G-3' tiRNA LysTTT, promotes bladder cancer malignancy via regulating ANXA2 phosphorylation. A novel tsRNA, m7G-3' tiRNA LysTTT, promotes bladder cancer malignancy via regulating ANXA2 phosphorylation

Emerging evidence indicates that tRNA-derived small RNAs (tsRNAs) with the most abundant RNA modifications play an important role in many complex physiological and pathological processes. However, the biological function and regulation mechanism of modified tsRNA in cancer are still poorly understood. Here, we screened and confirmed a novel m7G modified tsRNA, m7G-3'tiRNA LysTTT (mtiRL) in a variety of chemical carcinogenic models by combined small RNA sequencing with m7G small RNA modified Chip. Moreover, we found that mtiRL catalyzed by tRNA m7G modifying enzyme mettl1 promoted bladder cancer malignancy in vitro and in vivo. Mechanistically, mtiRL specifically bound to oncoprotein Annexin A2 (ANXA2) to promote Tyr24 phosphorylation of ANXA2 by enhancing interactions between ANXA2 and YES1, leading to ANXA2 activation and increased ANXA2 nuclear distribution in bladder cancer cells. Together, these findings define a critical role for mtiRL, targeting this novel m7G modified tsRNA would be an efficient way for the treatment of BC. Overall design: T24: Bladder cancer cells; T24-KO-M1: METTL1-knockout bladder cancer cells