Mechanism of chemoresistance in malignant gliomas via active enhancers

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K18386
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Aichi Cancer Center Research Institute (2020); Nagoya University (2019)
• Principal Investigator: Hirano Masaki 愛知県がんセンター(研究所), 分子腫瘍学分野, 研修生 (40823076)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: glioblastoma / RET finger protein / active cis-element / epigenetics / chemoresistance

Outline of Final Research Achievements

RET finger protein (RFP) forms a complex with histone deacetylase 1, resulting in aberrant deacetylation of H3K27ac and dysregulation of cis-regulatory elements. We evaluated the modulatory effects of RFP knockdown (KD) on cis-regulatory elements, gene expression, and chemosensitivity to temozolomide
both in glioblastoma cells and in intracranial glioblastoma model. Combination of RFP KD and TMZ markedly suppressed glioblastoma cell growth due to oxidative stress and aberrant cell cycle and increased survival time in mice with glioblastoma. ChIP-seq and RNA-seq revealed that RFP KD altered activity of numerous cis-regulatory elements adjacent to genes that control functions such as apoptosis, mitosis, DNA replication and cell cycle. This study suggests that RFP contributes to chemoresistance via aberrant deacetylation of H3K27, whereas dysregulation of RFP-associated cis-regulatory elements in glioma and RFP KD combined with TMZ is an effective treatment strategy for lethal glioma.

Free Research Field

悪性脳腫瘍

Academic Significance and Societal Importance of the Research Achievements

近年、脳腫瘍領域でもゲノム解析が進み、その発生に重要な遺伝子異常が明らかとなりつつある。しかし依然として悪性脳腫瘍が難治であることに変わりはなく、新規治療法開発が望まれている。
本研究では、エピゲノム調整関連因子であるRFPを標的とすることで、広範なエピゲノム変化が起こり、悪性脳腫瘍の化学療法抵抗性に寄与する限定的なパスウェイが阻害され、非常に高い治療効果が得られることが明らかとなった。今後、脳腫瘍患者の予後を改善する新規治療薬の開発につながると期待される。