title: Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia.
abstract: Besides the conventional carbon sources, acetyl-CoA has recently been shown to be generated from acetate in various types of cancers, where it promotes lipid synthesis and tumour growth. The underlying mechanism, however, remains largely unknown. We find that acetate induces a hyperacetylated state of histone H3 in hypoxic cells. Acetate predominately activates lipogenic genes ACACA and FASN expression by increasing H3K9, H3K27 and H3K56 acetylation levels at their promoter regions, thus enhancing de novo lipid synthesis, which combines with its function as the metabolic precursor for fatty acid synthesis. Acetyl-CoA synthetases (ACSS1, ACSS2) are involved in this acetate-mediated epigenetic regulation. More importantly, human hepatocellular carcinoma with high ACSS1/2 expression exhibit increased histone H3 acetylation and FASN expression. Taken together, this study demonstrates that acetate, in addition to its ability to induce fatty acid synthesis as an immediate metabolic precursor, also functions as an epigenetic metabolite to promote cancer cell survival under hypoxic stress.
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.|School of Life Science, Fudan University, Shanghai 200433, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.|State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong 999077, China.
authors.forename: Shu-Hai
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ren
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.|School of Life Science, Fudan University, Shanghai 200433, China.
authors.forename: Jin-Tao
authors.initials: JT
authors.lastname: Li
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Jia-Jia
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Chuan-Bo
authors.initials: CB
authors.lastname: Yao
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong 999077, China.
authors.forename: Shu-Xia
authors.initials: SX
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.|Department of Chemistry, Fudan University, Shanghai 200032, China.
authors.forename: Guo-Quan
authors.initials: GQ
authors.lastname: Yan
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.|School of Life Science, Fudan University, Shanghai 200433, China.
authors.forename: Di
authors.initials: D
authors.lastname: Wang
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong 999077, China.
authors.forename: Zongwei
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Xu
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Yu
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Peng-Yuan
authors.initials: PY
authors.lastname: Yang
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Qun-Ying
authors.initials: QY
authors.lastname: Lei
mesh_terms: D000106:Acetate-CoA Ligase / Q000378:metabolism; D000085:Acetates / Q000378:metabolism*; D000107:Acetylation; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002470:Cell Survival; D044127:Epigenesis, Genetic; D054890:Fatty Acid Synthase, Type I / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D051548:Histone Acetyltransferases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D050155:Lipogenesis; D008113:Liver Neoplasms / Q000378:metabolism*
chemical_list: D000085:Acetates; D006657:Histones; D051548:Histone Acetyltransferases; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; C000595379:ACSS2 protein, human; D000106:Acetate-CoA Ligase