Lysine Acetylation Activates 6-Phosphogluconate Dehydrogenase to Promote Tumor Growth

Changliang Shan; Shannon Elf; Quanjian Ji; Hee-Bum Kang; Lu Zhou; Taro Hitosugi; Lingtao Jin; Ruiting Lin; Liang Zhang; Jae Ho Seo; Jianxin Xie; Meghan Tucker; Ting-Lei Gu; Jessica Sudderth; Lei Jiang; Ralph J. DeBerardinis; Shaoxiong Wu; Yuancheng Li; Hui Mao; Peng Chen; Dongsheng Wang; Georgia Chen; Sagar Lonial; Martha Arellano; Hanna Khoury; Fadlo Khuri; Benjamin H. Lee; Daniel Brat; Keqiang Ye; Titus J. Boggon; Chuan He; Sumin Kang; Jun Fan; Jing Chen

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Author Notes:

Correspondence: jfan3@emory.edu (J.F.), or jchen@emory.edu (J.C.).

C.S. and S.E. contributed equally to this work.

J.X., T.-L.G., K.Y., P.C., D.J.B., M.L.A., S.L., H.J.K. and F.R.K. provided critical reagents.

M.T. and T.-L.G. performed mass spectrometry based assays.

Q.J., L. Zhou, L. Zhang and C.H. performed biochemical analysis of lysine-acetylated 6PGD and molecular docking studies and analyzed the data.

J.S., L.J., M.M., R.J.D., S.W., Y.L. and H.M. performed quantitative mass spectrometry and NMR based assays, and analyzed data.

B.H.L. performed the histopathological analyses.

T.J.B. performed structural analyses.

D.W. and G.Z.C. helped with xenograft experiments.

C.S., S.E., H.-B.K., J.-H.S. T.H., and J.F. performed all other experiments.

C.S., S.E., H.-B.K., S.K., J.F. and J.C. designed the study and wrote the paper.

J.F. and J.C. are senior authors and jointly managed the project.

All authors read and approved the final manuscript.

We thank Susan Sunay at the Hematology Division Tissue Bank, Winship Cancer Institute of Emory for providing primary tissue samples from leukemia patients.

J.X., M.T. and T.-L.G. are employees of Cell Signaling Technology, Inc.

H.J.K., F.R.K., S.K. and J.C. are Georgia Cancer Coalition Distinguished Cancer Scholars.

S.K. is a Robbins Scholar.

S.K. and J.C. are American Cancer Society Basic Research Scholars.

J.C. is a Scholar of the Leukemia and Lymphoma Society.

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Research Funding:

This work was supported in part by NIH grants CA140515, CA183594, CA174786 (J.C.), CA175316 (S.K.), GM071440 (C.H.) and the Pharmacological Sciences Training Grant T32 GM008602 (S.E.), DoD grant W81XWH-12-1-0217 (J.C.), National Natural Science Funds of China No.20902013 (L.Z.), Charles Harris Run For Leukemia, Inc. (H.J.K.) and the Hematology Tissue Bank of the Emory University School of Medicine and the Georgia Cancer Coalition (H.J.K.).

Keywords:

Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
TYROSINE PHOSPHORYLATION
METABOLISM

Lysine Acetylation Activates 6-Phosphogluconate Dehydrogenase to Promote Tumor Growth

Changliang Shan, Emory University

Shannon Elf, Emory University

Quanjian Ji, University of Chicago

Hee-Bum Kang, Emory University

Lu Zhou, University of Chicago

Taro Hitosugi, Emory University

Lingtao Jin, Emory University

Ruiting Lin, Emory University

Liang Zhang, University of Chicago

Jae Ho Seo, Emory University

Jianxin Xie, Cell Signaling Technology, Inc.

Meghan Tucker, Cell Signaling Technology, Inc.

Ting-Lei Gu, Cell Signaling Technology, Inc.

Jessica Sudderth, University of Texas Southwestern

Lei Jiang, University of Texas Southwestern

Ralph J. DeBerardinis, University of Texas Southwestern

Shaoxiong Wu, Emory University

Yuancheng Li, Emory University

Hui Mao, Emory University

Peng Chen, Peking University

Dongsheng Wang, Emory University

Georgia Chen, Emory University

Sagar Lonial, Emory University

Martha Arellano, Emory University

Hanna Khoury, Emory University

Fadlo Khuri, Emory University

Benjamin H. Lee, Novartis Institutes for BioMedical Research

Daniel Brat, Emory University

Keqiang Ye, Emory University

Titus J. Boggon, Yale University

Chuan He, University of Chicago

Sumin Kang, Emory University

Jun Fan, Emory University

Jing Chen, Emory University

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Journal Title:

Molecular Cell

Volume:

Volume 55, Number 4

Publisher:

Elsevier (Cell Press): 12 month embargo | 2014-08-21, Pages 552-565

Type of Work:

Article | Post-print: After Peer Review

Permanent URL:

https://pid.emory.edu/ark:/25593/v0nzp

Publisher DOI:

http://doi.org/10.1016/j.molcel.2014.06.020

Abstract:

Although the oxidative pentose phosphate pathway is important for tumor growth, how 6-phosphogluconate dehydrogenase (6PGD) in this pathway is upregulated in human cancers is unknown. We found that 6PGD is commonly activated in EGF-stimulated cells and human cancer cells by lysine acetylation. Acetylation at K76 and K294 of 6PGD promotes NADP+ binding to 6PGD and formation of active 6PGD dimers, respectively. Moreover, we identified DLAT and ACAT2 as upstream acetyltransferases of K76 and K294, respectively, and HDAC4 as the deacetylase of both sites. Expressing acetyl-deficient mutants of 6PGD in cancer cells significantly attenuated cell proliferation and tumor growth. This is due in partto reduced levels of 6PGD products ribulose-5-phosphate and NADPH, which led to reduced RNA and lipid biosynthesis as well as elevated ROS. Furthermore, 6PGD activity is upregulated with increased lysine acetylation in primary leukemia cells from human patients, providing mechanistic insights into 6PGD upregulation in cancer cells.

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This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Lysine Acetylation Activates 6-Phosphogluconate Dehydrogenase to Promote Tumor Growth

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