Diacylglycerol kinase γ predicts prognosis and functions as a tumor suppressor by negatively regulating glucose transporter 1 in hepatocellular carcinoma

Diacylglycerol kinases (DGK) are a family of enzymes catalyzing the transformation of diacylglycerol into phosphatidic acid, which have been recognized as key regulators in cell signaling pathways. The role of DGKγ in human malignancies has seldom been studied. In this study, we investigated the role of DGKγ in hepatocellular carcinoma (HCC). We found that DGKγ was down-regulated in HCC tumor tissues and cell lines as compared to that in non-tumor tissues. The prognostic value of DGKγ expression was evaluated by Cox regression and Kaplan-Meier analyses. Lower DGKγ expression in tumor tissues was an independent prognostic factor for poor post-surgical overall survival. By using HDACs inhibitors treatment and ChIP-PCR, we discovered that histone H3 and H4 deacetylation mainly contributed to the downregulation of DGKγ expression. Functional studies revealed that ectopic expression of DGKγ inhibited cell proliferation and cell migration in HCC cells. Mechanism studies showed that DGKγ overexpression led to down regulation of GLUT1 protein level and AMPK activity, which result in glucose uptake suppression as well as lactate and ATP production declination. The decrease of GLUT1 level could be partially rescued by treatments with either DGK inhibitor and lysosome inhibitor, indicating DGKγ may down-regulate GLUT1 through its kinase activity and lysosome degradation process. Together, this study demonstrated that DGKγ plays a tumor suppressor role in HCC by negatively regulating GLUT1. DGKγ could be a novel prognostic indicator and therapeutic target for HCC.