Researchers identify a specific cholesterol metabolic pathway in HCC

Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third leading cause of cancer-related deaths in the world. The human liver is the central organ for cholesterol homeostasis. Oxysterols are important metabolites from cholesterol, and they exhibit biological activities in many biological processes. However, excess oxysterols are very toxic to cells. Therefore, under physiological conditions, excess oxysterols in all extrahepatic tissues are transported to the liver for further metabolism. HCCs impair certain cellular functions of the liver and cause pathological alterations in many processes including cholesterol metabolism. However, the pathological role of altered cholesterol metabolism in HCC development is still unclear.

By investigating tissue samples from HCC patients and HCC cell lines, Dr. Ming Lu, Ph. D student Xi-Han Hu and their colleagues, led by Prof. LI Boliang at Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, find that a specific cholesterol metabolic pathway, involving induction of ACAT2 and esterification of excess oxysterols for secretion to avoid cytotoxicity, is established in a subset of HCCs for tumor growth. Inhibiting ACAT2 leads to the intracellular accumulation of unesterified oxysterols and suppresses the growth of both HCC cell lines and their xenograft tumors. Further mechanistic studies reveal that HCC-linked promoter hypomethylation is essential for the induction of human ACAT2 gene expression. This study demostrates a specific cholesterol metabolic pathway and its role in HCC tumor growth, and suggests that this cholesterol metabolic pathway may serve as an attractive target for HCC treatment.

This study entitled “A specific cholesterol metabolic pathway is established in a subset of HCCs for tumor growth” was published online in Journal of Molecular Cell Biology on October 26, 2013. It was supported by grants from the Ministry of Science and Technology of China and National Natural Science Foundation of China.