N1-methyladenosine methylation in mRNAs drives bladder cancer progression

Abstract With the growing recognition of RNA modification as a hallmark of cancer, N1-methyladenosine (m1A) methylation has been reported as a key mechanism of post-transcriptional regulation. However, the molecular mechanisms underlying m1A modification in bladder cancer (BLCA) progression remain unclear. In the current study, we aimed to explore the role of m1A methylation in BLCA. We found that the expression of the m1A methyltransferase TRMT61A was significantly elevated in human BLCA tissues. TRMT61A inhibition attenuated BLCA cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Mechanistically, transcriptional profiling identified heme oxygenase-2 (HMOX2) as an m1A modification target of TRMT61A, and HMOX2 mRNA m1A modifications were reduced in TRMT61A-deficient cells. TRMT61A promoted HMOX2 mRNA stabilization in a YTHDF1-dependent manner, and YTHDF1 knockdown decreased the stability of HMOX2 mRNA through an m1A modification-dependent mechanism, leading to the inhibition of tumor cell proliferation. Moreover, NF-κB was found to bind to the promoter region of TRMT61A and stimulate its expression. NF-κB activation also increased the nuclear translocation of TRMT61A. Together, our results demonstrate the oncogenic role of TRMT61A and the m1A modification-mediated NF-κB/TRMT61A/HMOX2 signaling pathway activation in BLCA, thus highlighting a novel therapeutic target for this disease.