Given that there is limited efficacy of available inhibitors for epigenetic abnormality in HCC therapy and there exists DNMT3a-TET2 coordination in CSCs, disruption of DNMT3a-TET2 interplay could be used in a neo-adjuvant manner to prevent emergence of resistant oncospheres or eradicate sorafenib-resistant cells. The gene discussed is TET2; the disease is hepatocellular carcinoma.