2021 Fiscal Year Final Research Report
CpG island methylator phenotype is induced by SWI/SNF defects in gastric cancers
Project/Area Number |
19K08456
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 53010:Gastroenterology-related
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Research Institution | National Cancer Center Japan |
Principal Investigator |
Yamada Harumi 国立研究開発法人国立がん研究センター, 研究所, 研究員 (10769425)
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Project Period (FY) |
2019-04-01 – 2022-03-31
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Keywords | CIMP / DNAメチル化 / ARID1A / クロマチンリモデリング / エピジェネティクス |
Outline of Final Research Achievements |
Mutations of SWI/SNF components, especially ARID1A, was associated with the CIMP, as well as EBV infection, in gastric cancers, and also in uterine endometrial and colorectal cancers, which are not affected by EBV infection. Genome-wide DNA methylation analysis showed that ARID1A knockout (KO) in cultured 293FT cells and gastric epithelial cells, GES1, induced aberrant DNA methylation of a substantial number of CpG sites. DNA methylation was induced at genomic regions with high levels of pre-existing histone H3 lysine 27 trimethylation (H3K27me3) and those with acquired H3K27me3 by ARID1A KO. These results showed that the ARID1A mutation induced aberrant DNA methylation, and this is likely to be one of the potential mechanisms of CIMP induction.
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Free Research Field |
がんエピジェネティクス
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Academic Significance and Societal Importance of the Research Achievements |
CIMPは予後や薬剤感受性など癌の臨床的特徴と相関し、癌治療戦略において重要な形質である。しかし、膠芽腫や大腸癌を除く癌では、その誘発機構は不明である。ARID1Aはがん抑制遺伝子として広く知られており、胃がんをはじめとする様々ながんにおいて、予後との関連や治療標的としての報告が多数存在する。しかしながら、CIMP誘発の原因遺伝子としての報告はなかった。 本研究により、ARID1A機能異常が胃がんにおけるCIMP誘発の一因となっていることが示唆された。
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