Similarly, the "frequent up-regulation of G9a in various HCC sample cohorts has also been confirmed and verified. In this study, upregulation of G9a was found to be related with HCC disease progression, cancer aggressiveness, and the development of more malignant tumour phenotypes. The functional analysis revealed that shRNA knockdown and CRISPR/Cas9 deletion of G9a both decreased HCC cell proliferation in vitro and affected the tumorigenicity of xenograft HCC in vivo when administered subcutaneously. The depletion of G9a resulted in a substantial reduction in HCC cell migratory capacity as well as the induction of cell senescence. The pharmacological inhibition of G9a by small molecule inhibitors UNC0638 and BIX01294 resulted in a reduction in HCC cell proliferation as well as a change in the shape of the cells. We demonstrated that the frequent up-regulation of G9a in human HCC was caused by gene copy number increase on chromosome 6p21 and the loss of miR-1, as demonstrated by mechanistic studies. Also of note, up-regulation of G9 epigenetically suppressed miR-1 production, resulting in the formation of a feedforward regulatory loop between the two genes. In human HCC, we discovered a putative tumour suppressor RARRES that was epigenetically silenced by G9a" and enhanced tumour cell proliferation. We discovered this by using RNA-Seq and GSEA analysis. We discovered that SETDB1 and "G9a are new oncogenes that are commonly up-regulated in human HCCs when the findings were taken together. It was discovered that their upregulationin human HCCs was caused by a variety of processes occurring at the chromosomal, transcriptional, post-transcriptional, and post-translational levels. Their carcinogenic activities may also be linked to epigenetic silencing of tumour suppressors that are downstream of them. It appears that SETDB1 and" G9a may be potential therapeutic targets for the treatment of HCC, based on our findings.