期刊
MOLECULAR CELL
卷 55, 期 4, 页码 552-565出版社
CELL PRESS
DOI: 10.1016/j.molcel.2014.06.020
关键词
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资金
- NIH [CA140515, CA183594, CA174786, CA175316, GM071440]
- Pharmacological Sciences Training Grant [T32 GM008602]
- DoD [W81XWH-12-1-0217]
- National Natural Science Funds of China [20902013]
- Charles Harris Run For Leukemia, Inc.
- Hematology Tissue Bank of the Emory University School of Medicine
- Georgia Cancer Coalition
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.
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