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

• Type of Material: Article
• Authors: Xue Gao, Fudan University; Shu-Hai Lin, Shanghai Jiao Tong University; Feng Ren, Fudan University; Jin-Tao Li, Fudan University; Jia-Jia Chen, Fudan University; Chuan-Bo Yao, Fudan University; Hong-Bin Yang, Fudan University; Shu-Xia Jiang, Hong Kong Baptist University; Guo-Quan Yan, Fudan University; Di Wang, Fudan University; Yi Wang, Fudan University; Ying Liu, Fudan University; Zongwei Cai, Hong Kong Baptist University; Ying-Ying Xu, Fudan University; Jing Chen, Emory University; Wenqiang Yu, Fudan University; Peng-Yuan Yang, Fudan University; Qun-Ying Lei, Fudan University
• Language: English
• Date: 2016-06-01
• Publisher: Nature Publishing Group: Nature Communications
• Publication Version: Final Published Version
• Copyright Statement: © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/ncomms11960
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 7
• Start Page: 11960
• End Page: 11960
• Grant/Funding Information: This work was supported by MOST(2015CB910401 and 2013CB911201), NSFC (grant no. 81430057, 81225016, 31271454 and 21377106), Shanghai Key basic research program (12JC1401100), Scholar of ‘Dawn' Program of Shanghai Education Commission, Shanghai Outstanding Academic Leader (grant no. 13XD1400600), Cheung Kong Scholar's Program, and the Youth Science and Technology Leading Talent by MOST to Q.Y.L.
• Keywords: HISTONE ACETYLATION; ATP-CITRATE LYASE; OVARIAN-CANCER CELL; GENE-EXPRESSION; HEPATOCELLULAR-CARCINOMA; Science & Technology; Science & Technology - Other Topics; EPITHELIAL-MESENCHYMAL TRANSITION; TRANSCRIPTION FACTORS; Multidisciplinary Sciences; COA SYNTHETASE 2; TUMOR-GROWTH; FATTY-ACID SYNTHASE
• Research Categories: Health Sciences, Pathology; Biology, Molecular; Chemistry, Biochemistry

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.