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Author Notes:

Email: pyyang@fudan.edu.cn Email: qlei@gudan.edu.cn These authors contributed equally to this work.

X.G. performed part of the experiments, analysed the data and co-wrote the manuscript.

F.R., J.T.L. and C.B.Y. assisted in doing the experiments, data analysis and proofreading the manuscript.

S.H.L., J.J.C., P.Y.Y. and S.X.J. contributed to GC–MS analysis of lipid pool and 1H-NMR spectra of acetate.

J.J.C., Y.W., G.Q.Y. and P.Y.Y. contributed to MS analysis.

H.B.Y. contributed to analysis of human hepatocarcinoma cancer samples and proofreading the manuscript.

D.W. and Y.Y.X. contributed to performing experiments and proofreading the manuscript.

Y.L. contributed to analysis of IHC samples.

J.C. and W.Q.Y. contributed to proofreading the manuscript.

S.H.L., Z.W.C. and P.Y.Y. contributed to design MS experiment and data analysis.

Q.Y.L. conceived the idea, designed and supervised the study, analysed the data and co-wrote the manuscript.

We thank the members of the Fudan Cancer Metabolism Laboratory for participation throughout this study.

We also thank Biomedical Core Facility, Fudan University for technical support.

The authors declare no competing financial interests.

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Research Funding:

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:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • FATTY-ACID SYNTHASE
  • EPITHELIAL-MESENCHYMAL TRANSITION
  • OVARIAN-CANCER CELL
  • ATP-CITRATE LYASE
  • COA SYNTHETASE 2
  • HISTONE ACETYLATION
  • HEPATOCELLULAR-CARCINOMA
  • TRANSCRIPTION FACTORS
  • GENE-EXPRESSION
  • TUMOR-GROWTH

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

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Journal Title:

Nature Communications

Volume:

Volume 7

Publisher:

, Pages 11960-11960

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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