Novel regulation of gene expression in brain tumors identified

Study reveals how combination of two key enzymes promotes tumor cell formation and growth

Study results revealed previously unknown interplay between two key enzymes and a novel understanding of how brain cancer tumors form and spread, according to researchers at The University of Texas MD Anderson Cancer Center.

The study, led by Zhimin Lu, M.D., Ph.D., professor of Neuro-Oncology, identified a previously unreported linkage between two enzymes known as Gcn5 and alpha-ketoglutarate dehydrogenase (alpha-KGDH), providing important new information about a histone modification process called succinylation. Results were published in the Dec. 6 online issue of Nature.

Histones are proteins vital for gene regulation, and histone modifications are central to regulation of many chromosome-related processes, including DNA replication, transcription and repair. There are 16 known histone modifications, including succinylation. Lu’s team studied the alpha-KGDH-generated succinyl-coenzyme A, a molecule crucial for many biochemical reactions in protein, carbohydrate and lipid metabolism, as well as for providing energy to cells.

“Succinylation is a newly identified histone modification; however, the mechanism underlying histone succinylation and its functional consequences are unknown,” said Lu. “In our study, we demonstrated that alpha-KGDH, when coupled with Gcn5, induces histone succinylation and promotes tumor cell proliferation and tumor development.”

Gcn5 is an enzyme known as a histone acetyltransferase which delivers molecular components making up an acetyl group to histone genes, allowing the genes to be switched on or off. Histones and other proteins, when modified by this process known as acetylation, play critical roles in regulation of gene expression, typically resulting in increased gene expression.

“We demonstrated that alpha-KGDH interacts with Gcn5 in the cell nucleus and found that tumor cell proliferation and tumor growth were inhibited when alpha-KGDH was blocked from entering the cell nucleus or by disruption of Gcn5’s binding to succinyl-coenzyme A,” said Lu. “These findings underscore the significance of Gcn5-regulated gene expression coupled with the metabolic enzyme alpha-KGDH in tumor cell proliferation and formation.”

MD Anderson study team members included Yugang Wang, Ph.D., Rui Liu, Ph.D., Yan Xia, Ph.D., Jong-Ho Lee, Ph.D., Xin-jian Li, Ph.D., Yanhua Zheng, Ph.D., all of Neuro-Oncology; Lin Tan and Peiying Yang, Ph.D., General Oncology; and David Hawke, Ph.D., Molecular Pathology. Other participating institutions included Rice University, Houston; University of California, Berkeley; Houston Methodist Research Institute, Houston; People’s Hospital of Hangzhou Medical College, Hangzhou, China; Wenzhou Medical University, Wenzhou, China; Peking Union Medical College, Beijing; the Affiliated Hospital of Qingdao University, Qingdao, China; and Tsinghua University, Beijing.

The study was funded by the National Institutes of Health (2R01 CA109035, 1R01CA169603, 1R01NS089754, P30CA016672 and 2P50CA127001), the James S. McDonnell Foundation 21st Century Science Initiative in Brain Cancer Research Award (220020318), and the Welch Foundation (C-1565).