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

Xue Gao; Shuhai 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; Qun Ying Lei

doi:10.1038/ncomms11960

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

Xue Gao, Shuhai 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^*, Qun Ying Lei

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › peer-review

304 Citations (Scopus)

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.

Original language	English
Article number	11960
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11960
Publication status	Published - 30 Jun 2016

Scopus Subject Areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/ncomms11960

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@article{58fede1b875048f79bc57b2beb102568,

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.",

author = "Xue Gao and Shuhai Lin and Feng Ren and Li, {Jin Tao} and Chen, {Jia Jia} and Yao, {Chuan Bo} and Yang, {Hong Bin} and Jiang, {Shu Xia} and Yan, {Guo Quan} and Di Wang and Yi Wang and Ying Liu and Zongwei Cai and Xu, {Ying Ying} and Jing Chen and Wenqiang Yu and Yang, {Peng Yuan} and Lei, {Qun Ying}",

note = "Funding Information: 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. 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.",

year = "2016",

month = jun,

day = "30",

doi = "10.1038/ncomms11960",

language = "English",

volume = "7",

journal = "Nature Communications",

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T1 - Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia

AU - Gao, Xue

AU - Lin, Shuhai

AU - Ren, Feng

AU - Li, Jin Tao

AU - Chen, Jia Jia

AU - Yao, Chuan Bo

AU - Yang, Hong Bin

AU - Jiang, Shu Xia

AU - Yan, Guo Quan

AU - Wang, Di

AU - Wang, Yi

AU - Liu, Ying

AU - Cai, Zongwei

AU - Xu, Ying Ying

AU - Chen, Jing

AU - Yu, Wenqiang

AU - Yang, Peng Yuan

AU - Lei, Qun Ying

N1 - Funding Information: 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. 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.

PY - 2016/6/30

Y1 - 2016/6/30

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms11960

DO - 10.1038/ncomms11960

M3 - Journal article

C2 - 27357947

AN - SCOPUS:84977119276

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 11960

ER -

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

Abstract

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