Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation

Joyce V Lee; Alessandro Carrer; Supriya Shah; Nathaniel W Snyder; Shuanzeng Wei; Sriram Venneti; Andrew J Worth; Zuo-Fei Yuan; Hee-Woong Lim; Shichong Liu; Ellen Jackson; Nicole M Aiello; Naomi B Haas; Timothy R Rebbeck; Alexander Judkins; Kyoung-Jae Won; Lewis A Chodosh; Benjamin A Garcia; Ben Z Stanger; Michael D Feldman; Ian A Blair; Kathryn E Wellen

doi:10.1016/j.cmet.2014.06.004

Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation

Joyce V Lee, Alessandro Carrer, Supriya Shah, Nathaniel W Snyder, Shuanzeng Wei, Sriram Venneti, Andrew J Worth, Zuo-Fei Yuan, Hee-Woong Lim, Shichong Liu, Ellen Jackson, Nicole M Aiello, Naomi B Haas, Timothy R Rebbeck, Alexander Judkins, Kyoung-Jae Won, Lewis A Chodosh, Benjamin A Garcia, Ben Z Stanger, Michael D FeldmanIan A Blair, Kathryn E Wellen

270 Citations (Scopus)

Abstract

Summary Histone acetylation plays important roles in gene regulation, DNA replication, and the response to DNA damage, and it is frequently deregulated in tumors. We postulated that tumor cell histone acetylation levels are determined in part by changes in acetyl coenzyme A (acetyl-CoA) availability mediated by oncogenic metabolic reprogramming. Here, we demonstrate that acetyl-CoA is dynamically regulated by glucose availability in cancer cells and that the ratio of acetyl-CoA:coenzyme A within the nucleus modulates global histone acetylation levels. In vivo, expression of oncogenic Kras or Akt stimulates histone acetylation changes that precede tumor development. Furthermore, we show that Akt's effects on histone acetylation are mediated through the metabolic enzyme ATP-citrate lyase and that pAkt(Ser473) levels correlate significantly with histone acetylation marks in human gliomas and prostate tumors. The data implicate acetyl-CoA metabolism as a key determinant of histone acetylation levels in cancer cells.

Original language	English
Journal	Cell Metabolism
Volume	20
Issue number	2
Pages (from-to)	306-319
Number of pages	14
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2014.06.004
Publication status	Published - 5 Aug 2014
Externally published	Yes

Keywords

Acetyl Coenzyme A/metabolism
Acetylation/drug effects
Brain Neoplasms/metabolism
Cell Line, Tumor
Cluster Analysis
Coenzyme A/metabolism
Glioma/metabolism
Glucose/pharmacology
Histones/metabolism
Humans
Interleukin-3/pharmacology
Male
Phosphorylation/drug effects
Prostatic Neoplasms/metabolism
Proto-Oncogene Proteins c-akt/metabolism
ras Proteins/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2014.06.004

http://www.cell.com/article/S1550413114002691/pdf

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Lee, J. V., Carrer, A., Shah, S., Snyder, N. W., Wei, S., Venneti, S., Worth, A. J., Yuan, Z.-F., Lim, H.-W., Liu, S., Jackson, E., Aiello, N. M., Haas, N. B., Rebbeck, T. R., Judkins, A., Won, K.-J., Chodosh, L. A., Garcia, B. A., Stanger, B. Z., ... Wellen, K. E. (2014). Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metabolism, 20(2), 306-319. https://doi.org/10.1016/j.cmet.2014.06.004

Lee, JV, Carrer, A, Shah, S, Snyder, NW, Wei, S, Venneti, S, Worth, AJ, Yuan, Z-F, Lim, H-W, Liu, S, Jackson, E, Aiello, NM, Haas, NB, Rebbeck, TR, Judkins, A, Won, K-J, Chodosh, LA, Garcia, BA, Stanger, BZ, Feldman, MD, Blair, IA & Wellen, KE 2014, 'Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation', Cell Metabolism, vol. 20, no. 2, pp. 306-319. https://doi.org/10.1016/j.cmet.2014.06.004

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title = "Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation",

abstract = "Summary Histone acetylation plays important roles in gene regulation, DNA replication, and the response to DNA damage, and it is frequently deregulated in tumors. We postulated that tumor cell histone acetylation levels are determined in part by changes in acetyl coenzyme A (acetyl-CoA) availability mediated by oncogenic metabolic reprogramming. Here, we demonstrate that acetyl-CoA is dynamically regulated by glucose availability in cancer cells and that the ratio of acetyl-CoA:coenzyme A within the nucleus modulates global histone acetylation levels. In vivo, expression of oncogenic Kras or Akt stimulates histone acetylation changes that precede tumor development. Furthermore, we show that Akt's effects on histone acetylation are mediated through the metabolic enzyme ATP-citrate lyase and that pAkt(Ser473) levels correlate significantly with histone acetylation marks in human gliomas and prostate tumors. The data implicate acetyl-CoA metabolism as a key determinant of histone acetylation levels in cancer cells.",

keywords = "Acetyl Coenzyme A/metabolism, Acetylation/drug effects, Brain Neoplasms/metabolism, Cell Line, Tumor, Cluster Analysis, Coenzyme A/metabolism, Glioma/metabolism, Glucose/pharmacology, Histones/metabolism, Humans, Interleukin-3/pharmacology, Male, Phosphorylation/drug effects, Prostatic Neoplasms/metabolism, Proto-Oncogene Proteins c-akt/metabolism, ras Proteins/genetics",

author = "Lee, {Joyce V} and Alessandro Carrer and Supriya Shah and Snyder, {Nathaniel W} and Shuanzeng Wei and Sriram Venneti and Worth, {Andrew J} and Zuo-Fei Yuan and Hee-Woong Lim and Shichong Liu and Ellen Jackson and Aiello, {Nicole M} and Haas, {Naomi B} and Rebbeck, {Timothy R} and Alexander Judkins and Kyoung-Jae Won and Chodosh, {Lewis A} and Garcia, {Benjamin A} and Stanger, {Ben Z} and Feldman, {Michael D} and Blair, {Ian A} and Wellen, {Kathryn E}",

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AU - Lee, Joyce V

AU - Carrer, Alessandro

AU - Shah, Supriya

AU - Snyder, Nathaniel W

AU - Wei, Shuanzeng

AU - Venneti, Sriram

AU - Worth, Andrew J

AU - Yuan, Zuo-Fei

AU - Lim, Hee-Woong

AU - Liu, Shichong

AU - Jackson, Ellen

AU - Aiello, Nicole M

AU - Haas, Naomi B

AU - Rebbeck, Timothy R

AU - Judkins, Alexander

AU - Won, Kyoung-Jae

AU - Chodosh, Lewis A

AU - Garcia, Benjamin A

AU - Stanger, Ben Z

AU - Feldman, Michael D

AU - Blair, Ian A

AU - Wellen, Kathryn E

PY - 2014/8/5

Y1 - 2014/8/5

N2 - Summary Histone acetylation plays important roles in gene regulation, DNA replication, and the response to DNA damage, and it is frequently deregulated in tumors. We postulated that tumor cell histone acetylation levels are determined in part by changes in acetyl coenzyme A (acetyl-CoA) availability mediated by oncogenic metabolic reprogramming. Here, we demonstrate that acetyl-CoA is dynamically regulated by glucose availability in cancer cells and that the ratio of acetyl-CoA:coenzyme A within the nucleus modulates global histone acetylation levels. In vivo, expression of oncogenic Kras or Akt stimulates histone acetylation changes that precede tumor development. Furthermore, we show that Akt's effects on histone acetylation are mediated through the metabolic enzyme ATP-citrate lyase and that pAkt(Ser473) levels correlate significantly with histone acetylation marks in human gliomas and prostate tumors. The data implicate acetyl-CoA metabolism as a key determinant of histone acetylation levels in cancer cells.

AB - Summary Histone acetylation plays important roles in gene regulation, DNA replication, and the response to DNA damage, and it is frequently deregulated in tumors. We postulated that tumor cell histone acetylation levels are determined in part by changes in acetyl coenzyme A (acetyl-CoA) availability mediated by oncogenic metabolic reprogramming. Here, we demonstrate that acetyl-CoA is dynamically regulated by glucose availability in cancer cells and that the ratio of acetyl-CoA:coenzyme A within the nucleus modulates global histone acetylation levels. In vivo, expression of oncogenic Kras or Akt stimulates histone acetylation changes that precede tumor development. Furthermore, we show that Akt's effects on histone acetylation are mediated through the metabolic enzyme ATP-citrate lyase and that pAkt(Ser473) levels correlate significantly with histone acetylation marks in human gliomas and prostate tumors. The data implicate acetyl-CoA metabolism as a key determinant of histone acetylation levels in cancer cells.

KW - Acetyl Coenzyme A/metabolism

KW - Acetylation/drug effects

KW - Brain Neoplasms/metabolism

KW - Cell Line, Tumor

KW - Cluster Analysis

KW - Coenzyme A/metabolism

KW - Glioma/metabolism

KW - Glucose/pharmacology

KW - Histones/metabolism

KW - Humans

KW - Interleukin-3/pharmacology

KW - Male

KW - Phosphorylation/drug effects

KW - Prostatic Neoplasms/metabolism

KW - Proto-Oncogene Proteins c-akt/metabolism

KW - ras Proteins/genetics

U2 - 10.1016/j.cmet.2014.06.004

DO - 10.1016/j.cmet.2014.06.004

M3 - Journal article

C2 - 24998913

SN - 1550-4131

VL - 20

SP - 306

EP - 319

JO - Cell Metabolism

JF - Cell Metabolism

IS - 2

ER -

Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation

Abstract

Keywords

UN SDGs

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