Remodeling of altered epigenetic regulation via targeting epigenetic factor during glioma formation

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K20003
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurosurgery
• Research Institution: Nagoya University
• Principal Investigator: Ohka Fumiharu 名古屋大学, 医学系研究科, 助教 (10725724)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 悪性脳腫瘍 / エピゲノム異常

Outline of Final Research Achievements

We established MADM mouse model which generates malignant glioma spontaneously. From an early stage of tumor formation, expression level of EZH2 was highly upregulated. Using glioma cell lines which are derived from MADM mice tumors, we found that EZH2 inhibitor (EPZ6438) inhibited cell growth of tumor cells. Also MRI imaging revealed that both oral administration of EPZ6438 and genetic depletion of EZH2 inhibited tumor growth in MADM mice significantly. We harvested tumor tissue of EZH2 knock-out MADM mice tumors, EZH2-intact MADM mice tumors and normal mice brains. Gene expression analysis with microarray revealed that expression levels of genes which are associated with neuronal differentiation are retained by knock out of EZH2 gene. These data indicated that EZH2 plays pivotal roles in glioma formation via dysregulation of histone modifications.

Free Research Field

脳神経外科学（脳腫瘍）

Academic Significance and Societal Importance of the Research Achievements

悪性脳腫瘍に対する治療薬は未だ少なく、極めて予後不良疾患である。本研究では悪性脳腫瘍の一部のサブグループではエピゲノム因子であるEZH2が腫瘍形成に重要な役割を果たしており、EZH2を阻害することで腫瘍の増大を抑制することができた。細胞実験のみでなく動物実験でも有望な効果が見られており、予後不良である悪性脳腫瘍の有望な新規治療薬の候補として今後さらに研究を発展していくための基礎となる知見を得ることができたと考えられる。