Identification of a histone demethylase promoting colon tumor formation

2014 Fiscal Year Final Research Report

• Project/Area Number: 24590932
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: YUTAKA Yamaji 東京大学, 医学部附属病院, 臨床登録医 (40376455)
• Research Collaborator: TATEISHI Keisuke 東京大学, 医学部附属病院, 講師 (20396948)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 大腸がん / ヒストン修飾

Outline of Final Research Achievements

Histone modification is related to malignant features of neoplastic cells. We found that the knockdown of a histone demethylase KDM4C eliminated colonosphere formation.β-catenin upregulated KDM4C expression in colonospheres. Microarray analysis identified the JAG1 gene that codes for a notch ligand Jagged1 responsible for sphere formation as a target of KDM4C. KDM4C knockdown suppressed the expression of JAG1 gene, and the downregulation recapitulated the impaired colonosphere formation. JAG1 is also a target of β-catenin, and chromatin immunoprecipitation analysis showed the binding of β-catenin and KDM4C onto the JAG1 promoter during colonosphere formation. KDM4C knockdown inhibited the binding of β-catenin on the JAG1 promoter and blunted JAG1 expression in colonospheres. These data indicate that KDM4C maintains the sphere forming capacity in CRCs by mediating the β-catenin-dependent transcription of JAG1 in a feed-forward manner.

Free Research Field

消化器内科学