Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth

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. ChenDongsheng 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)552-565
Number of pages14
JournalMolecular Cell
Volume55
Issue number4
DOIs
StatePublished - Aug 21 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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