ZMYND8 promotes the growth and metastasis of hepatocellular carcinoma by promoting HK2-mediated glycolysis

The bromodomain protein zinc finger MYND-type containing 8 (ZMYND8) plays a critical role in human breast cancer. However, the expression and biological function of ZMYND8 in hepatocellular carcinoma (HCC) are poorly understood. In this study, ZMYND8 expression was found to be elevated in HCC based on the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases. Next, we confirmed that ZMYND8 was frequently overexpressed in HCC tissues compared with adjacent non-tumor tissues. The up-regulated level of ZMYND8 was also observed in HCC cell lines. Elevated ZMYND8 expression was correlated with unfavorable clinicopathological features and poor prognosis of HCC patients. Functionally, ectopic expression of ZMYND8 potentiated the proliferation, migration, and invasion of Hep3B cells. Conversely, ZMYND8 knockdown led to the reduced proliferation and invasiveness of HCCLM3 cells. ZMYND8 silencing restrained the growth of HCCLM3 cells in vivo. Mechanistically, ZMYND8 enhanced glucose consumption, lactate production, and ATP level in HCC cells. Pharmacological inhibition of glycolysis using 2-DG blocked the promoting effects of ZMYND8 on HCC cell proliferation and mobility. Furthermore, hexokinase 2 (HK2), a key enzyme of glycolysis, was identified as the downstream target of ZMYND8 in HCC cells. ZMYND8 promoted HK2 transcription by recruiting bromodomain containing 4 (BRD4) to its promoter. Knockdown of HK2 abrogated the oncogenic functions of ZMYND8 in HCC. Altogether, these data indicated that ZMYND8 promoted the growth and metastasis of HCC by promoting HK2mediated glycolysis and might serve as a promising biomarker and therapeutic target for HCC.

Automated summary

ZMYND8 is frequently overexpressed in hepatocellular carcinoma (HCC) and is associated with poor prognosis, promoting proliferation, migration, and invasion of HCC cells. By enhancing HK2-mediated glycolysis, ZMYND8 promotes the growth and metastasis of HCC.