Identification of a histone demethylase promoting colon tumor formation

• 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)
• Co-Investigator(Kenkyū-buntansha): 立石 敬介 東京大学, 医学部附属病院, 講師 (20396948)
• 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
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 大腸がん / ヒストン修飾 / 大腸癌 / エピジェネテイクス / KDM4C

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.

Research Products

• [Journal Article] Loss of histone demethylase KDM6B enhances aggressiveness of pancreatic cancer through downregulation of C/EBPα. (2014)
  • Author(s): Yamamoto K, Tateishi K, Kudo Y, Sato T, Yamamoto S, Miyabayashi K, Asaoka Y, Ijichi H, Hirata Y, Otsuka M, Nakai Y, Isayama H, Ikenoue T, Kurokawa M, Fukayama M, Kokudo N, Omata M and Koike K.
  • Journal Title: Carcinogenesis Volume: 35 Issue: 11 Pages: 2404-14
  • DOI: 10.1093/carcin/bgu136
  • Peer Reviewed / Open Access
• [Journal Article] Histone demethylase KDM4C regulates sphere formation by mediating the cross talk between Wnt and Notch pathways in colonic cancer cells. (2013)
  • Author(s): Yamamoto S, Tateishi K, Kudo Y, Yamamoto K, Isagawa T, Nagae G, Nakatsuka T, Asaoka Y, Ijichi H, Hirata Y, Otsuka M, Ikenoue T, Aburatani H, Omata M, Koike K.
  • Journal Title: Carcinogenesis Volume: 10 Issue: 10 Pages: 2380-8
  • DOI: 10.1093/carcin/bgt174
  • Peer Reviewed
• [Presentation] JHDM3C regulates sphere formation by mediating the crosstalk between Wnt and Notch pathways
  • Author(s): Shinzo Yamamoto, Keisuke Tateishi, Yotaro Kudo, Keisuke Yamamoto, Takayuki Isagawa, Genta Nagae, Takuma Nakatsuka, Yoshinari Asaoka, Hideaki Ijichi, Masao Omata, Hiroyuki Aburatani, and Kazuhiko Koike
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: ﾊﾟｼﾌｨｺ横浜