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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

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Journal Title:

Molecular Cell

Volume:

Volume 55, Number 4

Publisher:

, Pages 552-565

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2014 Elsevier Inc.

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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