Chromatin remodeling regulation involved in carcinogenesis and cancer therapy

2014 Fiscal Year Final Research Report

• Project Area: Coupling of replication, repair and transcription, and their common mechanism of chromatin remodeling
• Project/Area Number: 22131006
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: National Cancer Center Japan
• Principal Investigator: KOHNO Takashi 独立行政法人国立がん研究センター, 研究所, 分野長 (80280783)
• Co-Investigator(Kenkyū-buntansha): OGIWARA Hideaki 国立がん研究センター, 研究所, 研究員 (40568953)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Keywords: 合成致死 / クロマチン制御 / がん治療 / 遺伝子融合

Outline of Final Research Achievements

The purpose of this study was to elucidate the significance of dysregulation of chromatin remodeling and DNA break repair in carcinogenesis; and to propose a therapeutic strategy against cancers with chromatin remodeling dysregulation. Using an originally developed non-homologous end joining assay, a molecular process to start DNA strand break repair; histone acetylation by CBP/p300 leads to accumulation of SWI/SNF chromatin remodeling complex at DNA break sites. Molecular process of RET oncogene fusion driving carcinogenesis, consisting of DNA strand breaks and their illegitimate repair, was also elucidated. Lung cancers without driver oncogene aberrations preferentially showed inactivating mutations and loss/reduced expression of a chromatin remodeling gene, BRG1. BRM-ATPase, a paralog for BRG1, was identified as a therapeutic target by synthetic lethality against BRG-deficient cancer.

Free Research Field

がん個別化医療