Acetate dependence of tumors

Sarah A Comerford; Zhiguang Huang; Xinlin Du; Yun Wang; Ling Cai; Agnieszka Witkiewicz; Holly Walters; Mohammed N. Tantawy; Allie Fu; H. Charles Manning; Jay D Horton; Robert E Hammer; Steven L McKnight; Benjamin P Tu

doi:10.1016/j.cell.2014.11.020

Acetate dependence of tumors

Sarah A Comerford, Zhiguang Huang, Xinlin Du, Yun Wang, Ling Cai, Agnieszka Witkiewicz, Holly Walters, Mohammed N. Tantawy, Allie Fu, H. Charles Manning, Jay D Horton, Robert E Hammer, Steven L McKnight, Benjamin P Tu

Research output: Contribution to journal › Article › peer-review

406 Scopus citations

Abstract

Acetyl-CoA represents a central node of carbon metabolism that plays a key role in bioenergetics, cell proliferation, and the regulation of gene expression. Highly glycolytic or hypoxic tumors must produce sufficient quantities of this metabolite to support cell growth and survival under nutrient-limiting conditions. Here, we show that the nucleocytosolic acetyl-CoA synthetase enzyme, ACSS2, supplies a key source of acetyl-CoA for tumors by capturing acetate as a carbon source. Despite exhibiting no gross deficits in growth or development, adult mice lacking ACSS2 exhibit a significant reduction in tumor burden in two different models of hepatocellular carcinoma. ACSS2 is expressed in a large proportion of human tumors, and its activity is responsible for the majority of cellular acetate uptake into both lipids and histones. These observations may qualify ACSS2 as a targetable metabolic vulnerability of a wide spectrum of tumors.

Original language	English (US)
Pages (from-to)	1591-1602
Number of pages	12
Journal	Cell
Volume	159
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2014.11.020
State	Published - Dec 18 2014

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2014.11.020

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@article{ad0391bc28b449c19445409d960efbe7,

title = "Acetate dependence of tumors",

abstract = "Acetyl-CoA represents a central node of carbon metabolism that plays a key role in bioenergetics, cell proliferation, and the regulation of gene expression. Highly glycolytic or hypoxic tumors must produce sufficient quantities of this metabolite to support cell growth and survival under nutrient-limiting conditions. Here, we show that the nucleocytosolic acetyl-CoA synthetase enzyme, ACSS2, supplies a key source of acetyl-CoA for tumors by capturing acetate as a carbon source. Despite exhibiting no gross deficits in growth or development, adult mice lacking ACSS2 exhibit a significant reduction in tumor burden in two different models of hepatocellular carcinoma. ACSS2 is expressed in a large proportion of human tumors, and its activity is responsible for the majority of cellular acetate uptake into both lipids and histones. These observations may qualify ACSS2 as a targetable metabolic vulnerability of a wide spectrum of tumors.",

author = "Comerford, {Sarah A} and Zhiguang Huang and Xinlin Du and Yun Wang and Ling Cai and Agnieszka Witkiewicz and Holly Walters and Tantawy, {Mohammed N.} and Allie Fu and Manning, {H. Charles} and Horton, {Jay D} and Hammer, {Robert E} and McKnight, {Steven L} and Tu, {Benjamin P}",

note = "Funding Information: We thank B. Posner and the staff of the UTSW High-Throughput Screening Core Facility for assistance with the ACSS2 inhibitor screen; V. Vemireddy, E. Maher, R. Bachoo, S. Altschuler, and L. Wu for use of slide scanners; and E. Maher, R. Bachoo, and D. Nijhawan for helpful discussions. This work was supported by a Damon Runyon-Rachleff Innovation Award, Packard Fellowship, and a CPRIT High-Risk/High-Impact grant to B.P.T., R01CA185169 to B.P.T. and S.L.M., unrestricted funds provided to S.L.M. by an anonymous donor, and Excellence in Education funds (EEF) from UTSW to R.E.H. S.L.M. is the founder and Chairman of the Scientific Advisory Board, X.D. is an employee, B.P.T., S.A.C., and R.E.H. are consultants, and S.L.M., B.P.T., S.A.C., X.D., R.E.H., and L.C. are shareholders of Peloton Therapeutics, Inc. Publisher Copyright: {\textcopyright} 2014 Elsevier Inc. All rights reserved.",

year = "2014",

month = dec,

day = "18",

doi = "10.1016/j.cell.2014.11.020",

language = "English (US)",

volume = "159",

pages = "1591--1602",

journal = "Cell",

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T1 - Acetate dependence of tumors

AU - Comerford, Sarah A

AU - Huang, Zhiguang

AU - Du, Xinlin

AU - Wang, Yun

AU - Cai, Ling

AU - Witkiewicz, Agnieszka

AU - Walters, Holly

AU - Tantawy, Mohammed N.

AU - Fu, Allie

AU - Manning, H. Charles

AU - Horton, Jay D

AU - Hammer, Robert E

AU - McKnight, Steven L

AU - Tu, Benjamin P

N1 - Funding Information: We thank B. Posner and the staff of the UTSW High-Throughput Screening Core Facility for assistance with the ACSS2 inhibitor screen; V. Vemireddy, E. Maher, R. Bachoo, S. Altschuler, and L. Wu for use of slide scanners; and E. Maher, R. Bachoo, and D. Nijhawan for helpful discussions. This work was supported by a Damon Runyon-Rachleff Innovation Award, Packard Fellowship, and a CPRIT High-Risk/High-Impact grant to B.P.T., R01CA185169 to B.P.T. and S.L.M., unrestricted funds provided to S.L.M. by an anonymous donor, and Excellence in Education funds (EEF) from UTSW to R.E.H. S.L.M. is the founder and Chairman of the Scientific Advisory Board, X.D. is an employee, B.P.T., S.A.C., and R.E.H. are consultants, and S.L.M., B.P.T., S.A.C., X.D., R.E.H., and L.C. are shareholders of Peloton Therapeutics, Inc. Publisher Copyright: © 2014 Elsevier Inc. All rights reserved.

PY - 2014/12/18

Y1 - 2014/12/18

N2 - Acetyl-CoA represents a central node of carbon metabolism that plays a key role in bioenergetics, cell proliferation, and the regulation of gene expression. Highly glycolytic or hypoxic tumors must produce sufficient quantities of this metabolite to support cell growth and survival under nutrient-limiting conditions. Here, we show that the nucleocytosolic acetyl-CoA synthetase enzyme, ACSS2, supplies a key source of acetyl-CoA for tumors by capturing acetate as a carbon source. Despite exhibiting no gross deficits in growth or development, adult mice lacking ACSS2 exhibit a significant reduction in tumor burden in two different models of hepatocellular carcinoma. ACSS2 is expressed in a large proportion of human tumors, and its activity is responsible for the majority of cellular acetate uptake into both lipids and histones. These observations may qualify ACSS2 as a targetable metabolic vulnerability of a wide spectrum of tumors.

AB - Acetyl-CoA represents a central node of carbon metabolism that plays a key role in bioenergetics, cell proliferation, and the regulation of gene expression. Highly glycolytic or hypoxic tumors must produce sufficient quantities of this metabolite to support cell growth and survival under nutrient-limiting conditions. Here, we show that the nucleocytosolic acetyl-CoA synthetase enzyme, ACSS2, supplies a key source of acetyl-CoA for tumors by capturing acetate as a carbon source. Despite exhibiting no gross deficits in growth or development, adult mice lacking ACSS2 exhibit a significant reduction in tumor burden in two different models of hepatocellular carcinoma. ACSS2 is expressed in a large proportion of human tumors, and its activity is responsible for the majority of cellular acetate uptake into both lipids and histones. These observations may qualify ACSS2 as a targetable metabolic vulnerability of a wide spectrum of tumors.

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DO - 10.1016/j.cell.2014.11.020

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SN - 0092-8674

VL - 159

SP - 1591

EP - 1602

JO - Cell

JF - Cell

IS - 7

ER -

Acetate dependence of tumors

Abstract

ASJC Scopus subject areas

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