mTOR-dependent hypomethylator phenotype in glioblastoma

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07649
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: Masui Kenta 東京女子医科大学, 医学部, 准教授 (60747682)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 膠芽腫 / mTOR複合体 / エピジェネティクス / DNAメチル化 / 神経回路 / グルタミン酸代謝

Outline of Final Research Achievements

Aberrant DNA methylation pattern, especially global “hypomethylator phenotype”, is closely associated with oncogenesis, but the underlying mechanisms are not fully understood. We demonstrate that mechanistic target of rapamycin complex 2 (mTORC2), a core component of epidermal growth factor receptor (EGFR) signaling, down-regulates the expression of de novo DNA methyltransferase (DNMT3A) to induce global DNA hypomethylator phenotype in the brain cancer glioblastoma (GBM). Integrated analyses with next generation sequencing and comprehensive methylation array for rat and human GBM samples reveal that mTORC2-dependent DNA hypomethylation epigenetically rewires a network of glutamate metabolism, eventually fascilitating tumor cell survival. The findings nominate mTORC2 as a critical regulator of DNA hypomethylator phenotype in cancer cells as well as an exploitable target to interfere with cancer-promoting epigenetic and metabolic reprogramming.

Free Research Field

神経病理学

Academic Significance and Societal Importance of the Research Achievements

本研究は、悪性度が高く有効な治療法がない脳腫瘍である膠芽腫の病態を、エピゲノムの視点から解明し、新しい治療戦略の可能性を探索する独創的な試みである。細胞株やヒト組織を使った実験病理学的な手法に加えて、次世代シーケンスやメチル化アレイを用いた網羅的解析により、腫瘍細胞と神経細胞がグルタミン酸代謝を介してネットワークを形成するという基礎的な分子メカニズムが明らかとなり、診断・治療を含む臨床応用まで視野に入れた研究へと繋がる事が期待される。