CSCs with overexpression of DNMT3a and TET2 have higher potential to form oncospheres and have reduced sorafenib sensitivity; (2) clinically, upregulation of DNMT3a and TET2 predicts less favorable drug responses and worse prognosis in sorafenib-treated HCC patients; (3) mechanistically, we proved that the DNMT3a-TET2 complex binds target promoters and coordinately regulate TSGs and cell proliferation genes via DNA methylation-dependent or -independent manners (Fig. S8). Here, DNMT3A is linked to hepatocellular carcinoma.