| Literature DB >> 25042803 |
Changliang Shan1, Shannon Elf1, Quanjiang Ji2, Hee-Bum Kang1, Lu Zhou2, Taro Hitosugi1, Lingtao Jin1, Ruiting Lin1, Liang Zhang2, Jae Ho Seo1, Jianxin Xie3, Meghan Tucker3, Ting-Lei Gu3, Jessica Sudderth4, Lei Jiang4, Ralph J DeBerardinis4, Shaoxiong Wu5, Yuancheng Li6, Hui Mao6, Peng R Chen7, Dongsheng Wang1, Georgia Zhuo Chen1, Sagar Lonial1, Martha L Arellano1, Hanna J Khoury1, Fadlo R Khuri1, Benjamin H Lee8, Daniel J Brat9, Keqiang Ye9, Titus J Boggon10, Chuan He2, Sumin Kang1, Jun Fan11, Jing Chen12.
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.Entities:
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Year: 2014 PMID： 25042803 PMCID： PMC4142084 DOI： 10.1016/j.molcel.2014.06.020
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 17.970