tRNA methyltransferase DNMT2 promotes hepatocellular carcinoma progression and enhances Bortezomib resistance through inhibiting TNFSF10

The tRNA methyltransferase DNMT2 (TRDMT1) plays a crucial role in various biological functions; however, its role in Cancer, particularly in liver Cancer, remains incompletely understood. In this study, we demonstrate that high DNMT2 expression is negatively correlated with prognosis in clinical liver Cancer patients. A series of in vitro and in vivo experiments showed that DNMT2 promotes the proliferation, colony formation, and metastasis of hepatocellular carcinoma cells. We identified the pro-apoptotic gene TNFSF10 (TRAIL) as a downstream target of DNMT2, regulated by the N6-methyladenosine (m6A) demethylase FTO. Epigenetically, DNMT2 deletion increased FTO expression, leading to a reduction in m6A methylation levels. FTO upregulated TNFSF10 expression, significantly reducing the proliferation and metastasis of DNMT2-deficient hepatocellular carcinoma cells. Furthermore, DNMT2 deletion was shown to significantly upregulate chemokine expression in tumors. Finally, we demonstrated that the NF-κB Inhibitor Bortezomib further enhances DNMT2 deletion-induced Apoptosis in hepatocellular carcinoma cells. This study reveals DNMT2's role in liver Cancer and presents a new therapeutic target for future treatments.