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

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.

• Authors: Changliang Shan, Shannon Elf, Quanjiang 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 R Chen, Dongsheng Wang, Georgia Zhuo Chen, Sagar Lonial, Martha L Arellano, Hanna J Khoury, Fadlo R Khuri, Benjamin H Lee, Daniel J Brat, Keqiang Ye, Titus J Boggon, Chuan He, Sumin Kang, Jun Fan, Jing Chen
• Journal: Molecular cell (Mol Cell) Vol. 55 Issue 4 Pg. 552-65 (Aug 21 2014) ISSN: 1097-4164 [Electronic] United States
• PMID: 25042803 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• NADP
• Phosphogluconate Dehydrogenase
• Dihydrolipoyllysine-Residue Acetyltransferase
• Acetyl-CoA C-Acetyltransferase
• Histone Deacetylases
• Lysine

Topics

• Acetyl-CoA C-Acetyltransferase (metabolism)
• Acetylation
• Animals
• Cell Line, Tumor
• Dihydrolipoyllysine-Residue Acetyltransferase (metabolism)
• Gene Expression Regulation, Neoplastic
• Histone Deacetylases (metabolism)
• Humans
• Leukemia (metabolism, pathology)
• Lung Neoplasms (metabolism, pathology)
• Lysine (metabolism)
• Mice
• NADP (metabolism)
• Neoplasms, Experimental
• Phosphogluconate Dehydrogenase (metabolism)
• Protein Binding (physiology)
• Protein Multimerization