The role of metabolic and epigenetic heterogeneity in glioblastoma treatment

2016 Fiscal Year Final Research Report

• Project/Area Number: 15K19067
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Human pathology
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: Masui Kenta 東京女子医科大学, 医学部, 助教 (60747682)
• Research Collaborator: MISCHEL Paul
• Project Period (FY): 2015-04-01 – 2017-03-31
• Keywords: 悪性脳腫瘍 / Heterogeneity / mTORC2 / がん代謝 / エピジェネティクス / ヒストンアセチル化 / テロメア

Outline of Final Research Achievements

Intratumoral heterogeneity generates subpopulations of cancer cells with distinct genotypes and phenotypes, but the mechanisms how oncogenic signaling establishes functional heterogeneity remain to be elucidated. Here, we identify an unexpected central role for mTORC2 in creating epigenetic heterogeneity where it controls diverse histone acetylation by dynamically reprogramming intracellular metabolism. We show that mTORC2 promotes the production of acetyl-CoA as well as the subcellular translocation of histone modifying enzymes, and this in turn facilitates the transcription of telomerase components via histone acetylation at the promoter regions. These central features of activated mTORC2 signaling, acetylated histone marks and telomerase expression are inter-correlated in clinical samples, and maintain telomere length and self-renewal capacity in glioblastoma cells. These results identify a specific role for mTORC2 in regulating functional heterogeneity in cancer epigenetics.

Free Research Field

神経病理