[4-2]Lysine acetylation activates 6-phosphogluconate dehydrogenase to link oxidative PPP, LKB1-AMPK signaling, lipogenesis and tumor growth

报告题目:Lysine acetylation activates 6-phosphogluconate dehydrogenase to link oxidative PPP, LKB1-AMPK signaling, lipogenesis and tumor growth
报 告 人：山长亮 博士（Department of Hematology and Medical Oncology, Emory University School of Medicine）
报告时间：2015年4月2日（星期四）上午9:00
报告地点：独墅湖校区二期云轩楼2301室

报告摘要:
How cancer cells coordinate anabolic biosynthesis and redox homeostasis remains unclear. We found that 6-phosphogluconate dehydrogenase (6PGD) in the oxidative pentose phosphate pathway is commonly activated in human cancers by lysine acetylation. Acetylation at K76 by acetyltransferase DLAT, and K294 by acetyltransferase ACAT2, promotes NADP+-binding to 6PGD and formation of active 6PGD dimers, respectively, while HDAC4 deacetylates both lysine sites. Moreover, 6PGD provides a novel crosstalk between metabolic and signaling pathways to promote lipogenesis by controlling intracellular levels of its product ribulose-5-phosphate (Ru-5-P). Ru-5-P disrupts active LKB1 complex, leading to inhibition of AMPK and subsequent activation of acetyl-CoA carboxylase 1 and lipogenesis. Thus, besides decreased RNA biosynthesis, targeting 6PGD by shRNA, abolishment of lysine acetylation, or a novel 6PGD inhibitor Physcion, results in reduced Ru-5-P and NADPH levels, which lead to decreased lipogenesis and increased ROS level, respectively. Together these metabolic defects result in attenuated cancer cell proliferation and tumor growth.
报告人简介:
Dr. Changliang Shan received his Ph.D. degree in Biochemistry and Molecular biology from Nankai University, in 2011. Afterwards, he worked as a postdoctoral fellow at Department of Hematology and Medical Oncology, Emory University School of Medicine, where he was mainly responsible for the role of post-translational modifications including phosphorylation, acetylation and methlyation in human cancers, with a particular focus on oncogenesis and cancer metabolism.
The Warburg effect describes an interesting metabolism switch that cancer cells take up more glucose than normal tissue, yet use less glucose for energy production and favor a much less efficient metabolic mechanism called glycolysis. It remains unknown how crucial this is for initiation and disease progression in human cancers. Dr Shan has approached these questions by examining whether posttranslational modifications (phosphorylation, acetylation) of metabolic enzymes — commonly upregulated in tumors — regulates the Warburg effect to contribute to tumorigenesis and maintenance of the tumor.