Epigenetic silencing of <i>KCTD8</i> promotes hepatocellular carcinoma growth by activating PI3K/AKT signaling

<b>Aim:</b> The aim of current study is to explore the epigenetic changes and function of KCTD8 in human hepatocellular carcinoma (HCC). <b>Materials &amp; methods:</b> HCC cell lines and tissue samples were employed. Methylation specific PCR, flow cytometry, immunoprecipitation and xenograft mouse models were used. <b>Results:</b><i>KCTD8</i> was methylated in 44.83% (104/232) of HCC and its methylation may act as an independent poor prognostic marker. KCTD8 expression was regulated by DNA methylation. KCTD8 suppressed HCC cell growth both <i>in vitro</i> and <i>in vivo</i> via inhibiting PI3K/AKT pathway. <b>Conclusion:</b> Methylation of <i>KCTD8</i> is an independent poor prognostic marker, and epigenetic silencing of KCTD8 increases the malignant tendency in HCC. Epigenetic dysregulation is a new hallmark for cancer therapy. Classical epi-drugs are mainly targeting epigenetic regulators, without tumor cell specificity. Deep understanding the role of epigenetic regulation in cancer-related signaling pathways may provide novel therapeutic targets. <i>KCTD8</i> is frequently methylated in HCC. KCTD8 methylation is an independent poor prognostic biomarker in HCC. KCTD8 inhibits HCC cells growth both <i>in vitro</i> and <i>in vivo</i>. Epigenetic silencing of <i>KCTD8</i> activates PI3K/AKT signaling pathway in HCC. <i>KCTD8</i> is a novel tumor suppressor in HCC.