Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia

Xue Gao, Shu-Hai Lin, Feng Ren, Jin-Tao Li, Jia-Jia Chen, Chuan-Bo Yao, Hong-Bin Yang, Shu-Xia Jiang, Guo-Quan Yan, Di Wang, Yi Wang, Ying Liu, Zongwei Cai, Ying-Ying Xu, Jing Chen, Wenqiang Yu, Peng-Yuan Yang () and Qun-Ying Lei ()
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Xue Gao: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University
Shu-Hai Lin: Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Feng Ren: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University
Jin-Tao Li: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University
Jia-Jia Chen: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University
Chuan-Bo Yao: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University
Hong-Bin Yang: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University
Shu-Xia Jiang: State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University
Guo-Quan Yan: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University
Di Wang: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University
Yi Wang: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University
Ying Liu: School of Basic Medical Sciences, Fudan University
Zongwei Cai: State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University
Ying-Ying Xu: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University
Jing Chen: Winship Cancer Institute of Emory, Emory University School of Medicine
Wenqiang Yu: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University
Peng-Yuan Yang: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University
Qun-Ying Lei: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11960

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