Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth

Jun Fan; Ruiting Lin; Siyuan Xia; Dong Chen; Shannon E. Elf; Shuangping Liu; Yaozhu Pan; Haidong Xu; Zhiyu Qian; Mei Wang; Changliang Shan; Lu Zhou; Qun Ying Lei; Yuancheng Li; Hui Mao; Benjamin H. Lee; Jessica Sudderth; Ralph J. DeBerardinis; Guojing Zhang; Taofeek Owonikoko; Manila Gaddh; Martha L. Arellano; Hanna J. Khoury; Fadlo R. Khuri; Sumin Kang; Paul W. Doetsch; Sagar Lonial; Titus J. Boggon; Walter J. Curran; Jing Chen

doi:10.1016/j.molcel.2016.10.014

Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth

Jun Fan, Ruiting Lin, Siyuan Xia, Dong Chen, Shannon E. Elf, Shuangping Liu, Yaozhu Pan, Haidong Xu, Zhiyu Qian, Mei Wang, Changliang Shan, Lu Zhou, Qun Ying Lei, Yuancheng Li, Hui Mao, Benjamin H. Lee, Jessica Sudderth, Ralph J. DeBerardinis, Guojing Zhang, Taofeek OwonikokoManila Gaddh, Martha L. Arellano, Hanna J. Khoury, Fadlo R. Khuri, Sumin Kang, Paul W. Doetsch, Sagar Lonial, Titus J. Boggon, Walter J. Curran, Jing Chen

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

65 Scopus citations

Abstract

Mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) regulates pyruvate dehydrogenase complex (PDC) by acetylating pyruvate dehydrogenase (PDH) and PDH phosphatase. How ACAT1 is “hijacked” to contribute to the Warburg effect in human cancer remains unclear. We found that active, tetrameric ACAT1 is commonly upregulated in cells stimulated by EGF and in diverse human cancer cells, where ACAT1 tetramers, but not monomers, are phosphorylated and stabilized by enhanced Y407 phosphorylation. Moreover, we identified arecoline hydrobromide (AH) as a covalent ACAT1 inhibitor that binds to and disrupts only ACAT1 tetramers. The resultant AH-bound ACAT1 monomers cannot reform tetramers. Inhibition of tetrameric ACAT1 by abolishing Y407 phosphorylation or AH treatment results in decreased ACAT1 activity, leading to increased PDC flux and oxidative phosphorylation with attenuated cancer cell proliferation and tumor growth. These findings provide a mechanistic understanding of how oncogenic events signal through distinct acetyltransferases to regulate cancer metabolism and suggest ACAT1 as an anti-cancer target.

Original language	English (US)
Pages (from-to)	859-874
Number of pages	16
Journal	Molecular cell
Volume	64
Issue number	5
DOIs	https://doi.org/10.1016/j.molcel.2016.10.014
State	Published - Dec 1 2016

Keywords

Warburg effect
acetyl-CoA acetyltransferase 1
arecoline hydrobromide
cancer metabolism
cancer therapy
mitochondria
pyruvate dehydrogenase complex
tetramer formation
tyrosine phosphorylation

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2016.10.014

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Fan, J., Lin, R., Xia, S., Chen, D., Elf, S. E., Liu, S., Pan, Y., Xu, H., Qian, Z., Wang, M., Shan, C., Zhou, L., Lei, Q. Y., Li, Y., Mao, H., Lee, B. H., Sudderth, J., DeBerardinis, R. J., Zhang, G., ... Chen, J. (2016). Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth. Molecular cell, 64(5), 859-874. https://doi.org/10.1016/j.molcel.2016.10.014

Fan, J, Lin, R, Xia, S, Chen, D, Elf, SE, Liu, S, Pan, Y, Xu, H, Qian, Z, Wang, M, Shan, C, Zhou, L, Lei, QY, Li, Y, Mao, H, Lee, BH, Sudderth, J, DeBerardinis, RJ, Zhang, G, Owonikoko, T, Gaddh, M, Arellano, ML, Khoury, HJ, Khuri, FR, Kang, S, Doetsch, PW, Lonial, S, Boggon, TJ, Curran, WJ & Chen, J 2016, 'Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth', Molecular cell, vol. 64, no. 5, pp. 859-874. https://doi.org/10.1016/j.molcel.2016.10.014

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title = "Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth",

abstract = "Mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) regulates pyruvate dehydrogenase complex (PDC) by acetylating pyruvate dehydrogenase (PDH) and PDH phosphatase. How ACAT1 is “hijacked” to contribute to the Warburg effect in human cancer remains unclear. We found that active, tetrameric ACAT1 is commonly upregulated in cells stimulated by EGF and in diverse human cancer cells, where ACAT1 tetramers, but not monomers, are phosphorylated and stabilized by enhanced Y407 phosphorylation. Moreover, we identified arecoline hydrobromide (AH) as a covalent ACAT1 inhibitor that binds to and disrupts only ACAT1 tetramers. The resultant AH-bound ACAT1 monomers cannot reform tetramers. Inhibition of tetrameric ACAT1 by abolishing Y407 phosphorylation or AH treatment results in decreased ACAT1 activity, leading to increased PDC flux and oxidative phosphorylation with attenuated cancer cell proliferation and tumor growth. These findings provide a mechanistic understanding of how oncogenic events signal through distinct acetyltransferases to regulate cancer metabolism and suggest ACAT1 as an anti-cancer target.",

keywords = "Warburg effect, acetyl-CoA acetyltransferase 1, arecoline hydrobromide, cancer metabolism, cancer therapy, mitochondria, pyruvate dehydrogenase complex, tetramer formation, tyrosine phosphorylation",

author = "Jun Fan and Ruiting Lin and Siyuan Xia and Dong Chen and Elf, {Shannon E.} and Shuangping Liu and Yaozhu Pan and Haidong Xu and Zhiyu Qian and Mei Wang and Changliang Shan and Lu Zhou and Lei, {Qun Ying} and Yuancheng Li and Hui Mao and Lee, {Benjamin H.} and Jessica Sudderth and DeBerardinis, {Ralph J.} and Guojing Zhang and Taofeek Owonikoko and Manila Gaddh and Arellano, {Martha L.} and Khoury, {Hanna J.} and Khuri, {Fadlo R.} and Sumin Kang and Doetsch, {Paul W.} and Sagar Lonial and Boggon, {Titus J.} and Curran, {Walter J.} and Jing Chen",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = dec,

day = "1",

doi = "10.1016/j.molcel.2016.10.014",

language = "English (US)",

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pages = "859--874",

journal = "Molecular cell",

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T1 - Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth

AU - Fan, Jun

AU - Lin, Ruiting

AU - Xia, Siyuan

AU - Chen, Dong

AU - Elf, Shannon E.

AU - Liu, Shuangping

AU - Pan, Yaozhu

AU - Xu, Haidong

AU - Qian, Zhiyu

AU - Wang, Mei

AU - Shan, Changliang

AU - Zhou, Lu

AU - Lei, Qun Ying

AU - Li, Yuancheng

AU - Mao, Hui

AU - Lee, Benjamin H.

AU - Sudderth, Jessica

AU - DeBerardinis, Ralph J.

AU - Zhang, Guojing

AU - Owonikoko, Taofeek

AU - Gaddh, Manila

AU - Arellano, Martha L.

AU - Khoury, Hanna J.

AU - Khuri, Fadlo R.

AU - Kang, Sumin

AU - Doetsch, Paul W.

AU - Lonial, Sagar

AU - Boggon, Titus J.

AU - Curran, Walter J.

AU - Chen, Jing

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) regulates pyruvate dehydrogenase complex (PDC) by acetylating pyruvate dehydrogenase (PDH) and PDH phosphatase. How ACAT1 is “hijacked” to contribute to the Warburg effect in human cancer remains unclear. We found that active, tetrameric ACAT1 is commonly upregulated in cells stimulated by EGF and in diverse human cancer cells, where ACAT1 tetramers, but not monomers, are phosphorylated and stabilized by enhanced Y407 phosphorylation. Moreover, we identified arecoline hydrobromide (AH) as a covalent ACAT1 inhibitor that binds to and disrupts only ACAT1 tetramers. The resultant AH-bound ACAT1 monomers cannot reform tetramers. Inhibition of tetrameric ACAT1 by abolishing Y407 phosphorylation or AH treatment results in decreased ACAT1 activity, leading to increased PDC flux and oxidative phosphorylation with attenuated cancer cell proliferation and tumor growth. These findings provide a mechanistic understanding of how oncogenic events signal through distinct acetyltransferases to regulate cancer metabolism and suggest ACAT1 as an anti-cancer target.

AB - Mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) regulates pyruvate dehydrogenase complex (PDC) by acetylating pyruvate dehydrogenase (PDH) and PDH phosphatase. How ACAT1 is “hijacked” to contribute to the Warburg effect in human cancer remains unclear. We found that active, tetrameric ACAT1 is commonly upregulated in cells stimulated by EGF and in diverse human cancer cells, where ACAT1 tetramers, but not monomers, are phosphorylated and stabilized by enhanced Y407 phosphorylation. Moreover, we identified arecoline hydrobromide (AH) as a covalent ACAT1 inhibitor that binds to and disrupts only ACAT1 tetramers. The resultant AH-bound ACAT1 monomers cannot reform tetramers. Inhibition of tetrameric ACAT1 by abolishing Y407 phosphorylation or AH treatment results in decreased ACAT1 activity, leading to increased PDC flux and oxidative phosphorylation with attenuated cancer cell proliferation and tumor growth. These findings provide a mechanistic understanding of how oncogenic events signal through distinct acetyltransferases to regulate cancer metabolism and suggest ACAT1 as an anti-cancer target.

KW - Warburg effect

KW - acetyl-CoA acetyltransferase 1

KW - arecoline hydrobromide

KW - cancer metabolism

KW - cancer therapy

KW - mitochondria

KW - pyruvate dehydrogenase complex

KW - tetramer formation

KW - tyrosine phosphorylation

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DO - 10.1016/j.molcel.2016.10.014

M3 - Article

C2 - 27867011

AN - SCOPUS:85003697636

SN - 1097-2765

VL - 64

SP - 859

EP - 874

JO - Molecular cell

JF - Molecular cell

IS - 5

ER -

Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth

Abstract

Keywords

ASJC Scopus subject areas

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