Androgen Receptor Stimulates Hexokinase 2 and Induces Glycolysis by PKA/CREB Signaling in Hepatocellular Carcinoma

Abstract

Background: Hepatocellular carcinoma (HCC) escapes growth inhibition by upregulating hexokinase 2 (HK2); however, the mechanism by which tumor cells upregulate HK2 remains unclear. Aim: We aimed to investigate the role of androgen receptor (AR) signalling in promoting HK2 expression in HCC. Methods: The expressions of AR and HK2 in HCC tissues were analyzed by immunohistochemistry. Cell proliferation was determined using the CCK-8 assay, and the molecular mechanism of AR in the regulation of HK2 was evaluated by immunoblotting and luciferase assays. Results: AR expression is positively correlated with HK2 staining by an immunohistochemical analysis. The manipulation of AR expression changed HK2 expression and glycolysis. AR signaling promoted the growth of HCC by enhancing HK2-mediated glycolysis. Moreover, AR stimulated HK2 levels and glycolysis by potentiating protein kinase A/cyclic adenosine monophosphate response element-binding (CREB) protein signaling. CREB silencing decreased HK2 expression and inhibited AR-mediated HCC glycolysis. AR affected the sensitivity of HCC cells to glycolysis inhibitors by regulating downstream phosphorylated (p)-CREB. Conclusions: These results indicate that AR at least partially induced glycolysis via p-CREB regulation of HK2 in HCC cells. Thus, this pathway should be considered for the design of novel therapeutic methods to target AR-overexpressing HCC.