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Lysine Acetylation Activates 6-Phosphogluconate Dehydrogenase to Promote Tumor Growth

Shan, C and Elf, S and Ji, Q and Kang, HB and Zhou, L and Hitosugi, T and Jin, L and Lin, R and Zhang, L and Seo, JH and Xie, J and Tucker, M and Gu, TL and Sudderth, J and Jiang, L and DeBerardinis, RJ and Wu, S and Li, Y and Mao, H and Chen, PR and Wang, D and Chen, GZ and Lonial, S and Arellano, ML and Khoury, HJ and Khuri, FR and Lee, BH and Brat, DJ and Ye, K and Boggon, TJ and He, C and Kang, S and Fan, J and Chen, J (2014) Lysine Acetylation Activates 6-Phosphogluconate Dehydrogenase to Promote Tumor Growth. Molecular Cell.

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 part to 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

Item Type: Article
Additional Information: NIBR author: institute: NIBR contributor address: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USADepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USADepartment of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USADepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USADepartment of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USADepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USADepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USADepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USADepartment of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USADepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USACell Signaling Technology, Inc. (CST), Danvers, MA 01923, USACell Signaling Technology, Inc. (CST), Danvers, MA 01923, USACell Signaling Technology, Inc. (CST), Danvers, MA 01923, USAUT Southwestern Medical Center, Dallas, TX 75390, USAUT Southwestern Medical Center, Dallas, TX 75390, USAUT Southwestern Medical Center, Dallas, TX 75390, USADepartment of Chemistry, Emory University, Atlanta, GA 30322, USADepartment of Radiology, Emory University, Atlanta, GA 30322, USADepartment of Radiology, Emory University, Atlanta, GA 30322, USACollege of Chemistry and Molecular Engineering, Peking University, Beijing 100871, ChinaDepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USADepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USADepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USADepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USADepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USADepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USANovartis Institutes for BioMedical Research, Cambridge, MA 02139, USADepartment of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USADepartment of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USADepartment of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USADepartment of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USADepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USADepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA. Electronic address: jfan3@emory.eduDepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA. Electronic address: jchen@emory.edu
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/23415

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