title: A specific cholesterol metabolic pathway is established in a subset of HCCs for tumor growth.
abstract: The liver plays a central role in cholesterol homeostasis. It exclusively receives and metabolizes oxysterols, which are important metabolites of cholesterol and are more cytotoxic than free cholesterol, from all extrahepatic tissues. Hepatocellular carcinomas (HCCs) impair certain liver functions and cause pathological alterations in many processes including cholesterol metabolism. However, the link between an altered cholesterol metabolism and HCC development is unclear. Human ACAT2 is abundantly expressed in intestine and fetal liver. Our previous studies have shown that ACAT2 is induced in certain HCC tissues. Here, by investigating tissue samples from HCC patients and HCC cell lines, we report 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 ACAT2 gene expression. We postulate that specifically blocking this HCC-established cholesterol metabolic pathway may have potential therapeutic applications for HCC patients.
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.forename: Xi-Han
authors.initials: XH
authors.lastname: Hu
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.forename: Guang-Jing
authors.initials: GJ
authors.lastname: Hu
authors.forename: Jia-Jia
authors.initials: JJ
authors.lastname: Xu
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Zhao
authors.forename: Xi-Xiao
authors.initials: XX
authors.lastname: Wei
authors.forename: Catherine C Y
authors.initials: CC
authors.lastname: Chang
authors.forename: Yin-Kun
authors.initials: YK
authors.lastname: Liu
authors.forename: Fa-Jun
authors.initials: FJ
authors.lastname: Nan
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Ta-Yuan
authors.initials: TY
authors.lastname: Chang
authors.forename: Bao-Liang
authors.initials: BL
authors.lastname: Song
authors.forename: Bo-Liang
authors.initials: BL
authors.lastname: Li
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000502:physiology; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays
chemical_list: D002784:Cholesterol
keywords: ACAT2; CpG methylation; HCC; inhibition of tumor growth; oxysterol secretion