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An investigation of histone modifications that modulate malignant properties of pancreatic cancer.

Research Project

Project/Area Number 24591009
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionThe University of Tokyo

Principal Investigator

YAMAMOTO Keisuke  東京大学, 医学部附属病院, 特任臨床医 (10608532)

Co-Investigator(Kenkyū-buntansha) TATEISHI Keisuke  東京大学, 医学部附属病院・消化器内科, 講師 (20396948)
伊地知 秀明  東京大学, 医学部附属病院, 講師 (70463841)
Co-Investigator(Renkei-kenkyūsha) IJICHI Hideaki  東京大学, 医学部附属病院・消化器内科/病態栄養治療部, 講師 (70463841)
Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥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膵癌 / ヒストン修飾 / エピジェネティクス
Outline of Final Research Achievements

In this study, we have identified a novel KDM6B-CEBPA axis and revealed its tumor-suppressive role in pancreatic ductal adenocarcinoma (PDAC). KDM6B is a histone demethylase for H3K27me3, a repressive chromatin mark. We found that KDM6B was highly expressed in pancreatic precancerous lesions PanINs, and that the expression of KDM6B decreased as the malignant grade progressed. Notably, knockdown of KDM6B in PDAC cells enhanced aggressiveness, as shown by increased peritoneal dissemination and liver metastasis in orthotopic transplantation model using nude mice. Microarray and chromatin immunoprecipitation analysis implicated CEBPA for aggressiveness induced by KDM6B knockdown. Indeed, CEBPA knockdown recapitulated the phenotypic change of PDAC cells after KDM6B knockdown. Moreover, similar expression patterns of KDM6B and CEBPA in PDAC emphasized their functional correlation. Together, our results propose a significant role for the KDM6B-CEBPA axis in the PDAC phenotype.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • 2012 Research-status Report
  • Research Products

    (3 results)

All 2014 2013

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (2 results)

  • [Journal Article] Loss of histone demethylase KDM6B enhances aggressiveness of pancreatic cancer through downregulation of C/EBPα2014

    • 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

    • DOI

      10.1093/carcin/bgu136

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] ヒストン脱メチル化酵素KDM6Bの発現低下はCEBPAの発現低下を介し膵癌の進展を促進する2014

    • Author(s)
      山本恵介、立石敬介、工藤洋太郎、佐藤智彦、松坂恵介、山本信三、宮林弘至、浅岡良成、伊地知秀明、中井陽介、伊佐山浩通、池上恒雄 、黒川峰夫、深山正久、國土典宏、小俣政男、小池和彦
    • Organizer
      第45回大会 日本膵臓学会大会
    • Place of Presentation
      北九州国際会議場
    • Year and Date
      2014-07-11 – 2014-07-12
    • Related Report
      2014 Annual Research Report
  • [Presentation] Reduced expression of histone demethylase KDM6B promotes pancreatic cancer progression through downregulation of C/EBPα.2013

    • Author(s)
      山本 恵介
    • Organizer
      American Association of Cancer Research Annual Meeting 2013
    • Place of Presentation
      Washingto, DC
    • Related Report
      2013 Research-status Report

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Published: 2013-05-31   Modified: 2019-07-29  

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