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Mol Cell. 2014 Aug 21;55(4):552-65. doi: 10.1016/j.molcel.2014.06.020. Epub 2014 Jul 17.

Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth.

Author information

1
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA.
2
Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
3
Cell Signaling Technology, Inc. (CST), Danvers, MA 01923, USA.
4
UT Southwestern Medical Center, Dallas, TX 75390, USA.
5
Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
6
Department of Radiology, Emory University, Atlanta, GA 30322, USA.
7
College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
8
Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
9
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA.
10
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
11
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA. Electronic address: jfan3@emory.edu.
12
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University, Atlanta, GA 30322, USA. Electronic address: jchen@emory.edu.

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.

PMID:
25042803
PMCID:
PMC4142084
DOI:
10.1016/j.molcel.2014.06.020
[Indexed for MEDLINE]
Free PMC Article

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