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

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357 Scopus citations

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
Pages (from-to)	306-319
Number of pages	14
Journal	Cell metabolism
Volume	20
Issue number	2
DOIs	https://doi.org/10.1016/j.cmet.2014.06.004
State	Published - Aug 5 2014

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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

@article{cb50cf14af3745d0a6f9cd9dc29815d7,

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.",

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 Yuan, {Zuo Fei} and Lim, {Hee Woong} and Shichong Liu and Ellen Jackson and Aiello, {Nicole M.} and Haas, {Naomi B.} and Rebbeck, {Timothy R.} and Alexander Judkins and Won, {Kyoung Jae} and Chodosh, {Lewis A.} and Garcia, {Benjamin A.} and Stanger, {Ben Z.} and Feldman, {Michael D.} and Blair, {Ian A.} and Wellen, {Kathryn E.}",

note = "Funding Information: This work was supported by grants from the Pew Charitable Trusts (Biomedical Scholar Award), the Elsa U. Pardee Foundation, the American Diabetes Association (7-12-JF-59), and University of Pennsylvania Start-up Funds, to K.E.W. I.A.B. was supported by NIH grants P30ES0138328 and T32ES019851. B.A.G. acknowledges funding from the National Science Foundation Early Faculty CAREER award and an NIH Innovator grant (DP2OD007447) from the Office of the Director. K.-J.W. acknowledges R21-DK098769 and the University of Pennsylvania Diabetes Research Center (DRC) P30-DK19525. We thank George Belka for assistance with mammary tissue sections, as well as Dan Martinez and Li-Ping Wang for technical assistance with human tissue IHC. We thank the Functional Genomics Core at DRC (P30-DK19525) for RNA sequencing. ",

year = "2014",

month = aug,

day = "5",

doi = "10.1016/j.cmet.2014.06.004",

language = "English",

volume = "20",

pages = "306--319",

journal = "Cell Metabolism",

issn = "1550-4131",

number = "2",

}

Lee, JV, Carrer, A, Shah, S, Snyder, NW, Wei, S, Venneti, S, Worth, AJ, Yuan, ZF, Lim, HW, Liu, S, Jackson, E, Aiello, NM, Haas, NB, Rebbeck, TR, Judkins, A, Won, KJ, 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

TY - JOUR

T1 - Akt-dependent metabolic reprogramming regulates tumor cell Histone acetylation

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.

N1 - Funding Information: This work was supported by grants from the Pew Charitable Trusts (Biomedical Scholar Award), the Elsa U. Pardee Foundation, the American Diabetes Association (7-12-JF-59), and University of Pennsylvania Start-up Funds, to K.E.W. I.A.B. was supported by NIH grants P30ES0138328 and T32ES019851. B.A.G. acknowledges funding from the National Science Foundation Early Faculty CAREER award and an NIH Innovator grant (DP2OD007447) from the Office of the Director. K.-J.W. acknowledges R21-DK098769 and the University of Pennsylvania Diabetes Research Center (DRC) P30-DK19525. We thank George Belka for assistance with mammary tissue sections, as well as Dan Martinez and Li-Ping Wang for technical assistance with human tissue IHC. We thank the Functional Genomics Core at DRC (P30-DK19525) for RNA sequencing.

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.

UR - http://www.scopus.com/inward/record.url?scp=84905816638&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2014.06.004

DO - 10.1016/j.cmet.2014.06.004

M3 - Article

C2 - 24998913

AN - SCOPUS:84905816638

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

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