Superenhancer-mediated RUNX3 overexpression in EB virus-associated tumorigenesis

• Project/Area Number: 16K14613
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Kumamoto University
• Principal Investigator: Osato Motomi 熊本大学, 国際先端医学研究機構, 特別招聘教授 (90314286)
• Project Period (FY): 2016-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 細胞不死化 / EBウイルス / スーパーエンハンサー / RUNX転写因子 / 癌 / 内科

Outline of Final Research Achievements

Epstein-Barr virus (EBV) is well known to be a causative pathogen for widespread types of cancers; however, the molecular basis for its tumorigenesis remains poorly understood. Recent studies by us and others demonstrated that superenhancer (SE)-driven overexpression of the RUNX3 gene may underlie EBV-associated tumorigenesis. To address this question, we first suppressed the SE activity by a SE inhibitor, JQ1. In the presence of JQ1, proliferation of EBV-positive B cell and NKT lymphoma cell lines was all strongly suppressed, due to the suppressed activity of SE and resultant decreased expression of RUNX3. The significance of SE was further confirmed by CRISPR/Cas9 mediated excision of the SE region. In addition, RUNX3 knockdown also led to similar suppression of cell proliferation. These results suggest that SE-driven overexpression of RUNX3 is a key mechanism for EBV-associated tumorigenesis and the inhibition of SE activity by drugs appears to be a novel therapeutic approach.

Research Products

• [Int'l Joint Research] National University of Singapore(Singapore)
• [Journal Article] Runx Family Genes in Tissue Stem Cell Dynamics. (2017)
  • Author(s): Wang CQ, Mok MM, Yokomizo T, Tergaonkar V, Osato M.
  • Journal Title: Adv Exp Med Biol. Volume: 962 Pages: 117-138
  • DOI: 10.1007/978-981-10-3233-2_9
  • ISBN: 9789811032318, 9789811032332
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Lack of Phenotypical and Morphological Evidences of Endothelial to Hematopoietic Transition in the Murine Embryonic Head during Hematopoietic Stem Cell Emergence. (2016)
  • Author(s): Iizuka K, Yokomizo T, Watanabe N, Tanaka Y, Osato M, Takaku T, Komatsu N.
  • Journal Title: PLoS One Volume: 11 Issue: 5 Pages: e0156427-e0156427
  • DOI: 10.1371/journal.pone.0156427
  • Peer Reviewed / Open Access
• [Journal Article] Cyclin A2 regulates erythrocyte morphology and numbers. (2016)
  • Author(s): Jayapal SR, Ang HY, Wang CQ, Bisteau X, Caldez MJ, Xuan GX, Yu W, Tergaonkar V, Osato M, Lim B, Kaldis P.
  • Journal Title: Cell Cycle Volume: 15 Issue: 22 Pages: 3070-3081
  • DOI: 10.1080/15384101.2016.1234546
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Identification of Stem Cells in the Epithelium of the Stomach Corpus and Antrum of Mice. (2016)
  • Author(s): Matsuo J, Kimura S, Yamamura A, Koh CP, Hossain MZ, Heng DL, Kohu K, Voon DC, Hiai H, Unno M, So JB, Zhu F, Srivastava S, Teh M, Yeoh KG, Osato M, Ito Y.
  • Journal Title: Gastroenterology Volume: 152 Issue: 1 Pages: 218-231
  • DOI: 10.1053/j.gastro.2016.09.018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activation of EVI1 transcription by the LEF1/β-catenin complex with p53-alteration in myeloid blast crisis of chronic myeloid leukemia. (2016)
  • Author(s): Manachai N, Saito Y, Nakahata S, Bahirvani AG, Osato M, Morishita K.
  • Journal Title: Biochem Biophys Res Commun Volume: 482 Issue: 4 Pages: 994-1000
  • DOI: 10.1016/j.bbrc.2016.11.146
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] LIN28B Activation by PRL-3 Promotes Leukemogenesis and a Stem Cell-like Transcriptional Program in AML. (2016)
  • Author(s): Zhou J, Chan ZL, Bi C, Lu X, Chong PS, Chooi JY, Cheong LL, Liu SC, Ching YQ, Zhou Y, Osato M, Tan TZ, Ng CH, Ng SB, Wang S, Zeng Q, Chng WJ.
  • Journal Title: Mol Cancer Res Volume: 15 Issue: 3 Pages: 294-303
  • DOI: 10.1158/1541-7786.mcr-16-0275-t
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia. (2016)
  • Author(s): Liau WS, Tan SH, Ngoc PC, Wang CQ, Tergaonkar V, Feng H, Gong Z, Osato M, Look AT, Sanda T.
  • Journal Title: Leukemia Volume: 印刷中 Issue: 8 Pages: 1798-1807
  • DOI: 10.1038/leu.2016.392
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC. (2016)
  • Author(s): Selvarajan V, Osato M, Nah GS, Yan J, Chung TH, Voon DC, Ito Y, Ham MF, Salto-Tellez M, Shimizu N, Choo SN, Fan S, Chng WJ, Ng SB.
  • Journal Title: Leukemia Volume: 印刷中 Issue: 10 Pages: 2219-2227
  • DOI: 10.1038/leu.2017.40
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] RUNX3エンハンサーeR3による腸上皮細胞間リンパ球の抗腫瘍効果制御機構 (2017)
  • Author(s): Osato M
  • Organizer: Cancer Research Institute of Kanazawa University symposium
  • Place of Presentation: Kanazawa, Japan
  • Year and Date: 2017-02-14
  • Invited
• [Presentation] Enhancer for Runx1, eR1: a powerful tool in stem cell and cancer biology (2016)
  • Author(s): Osato M
  • Organizer: 39th Annual Mtg of Molecular Biology Society of Japan
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2016-11-30
  • Int'l Joint Research / Invited
• [Presentation] Enhancer for Runx1, eR1: a powerful tool in stem cell and cancer biology (2016)
  • Author(s): Osato M
  • Organizer: 14th Stem Cell Res Symposium
  • Place of Presentation: Awaji, Japan
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Remarks] Mouse models for core binding factor leukemia
  • URL: http://ircms.kumamoto-u.ac.jp/publications/2015/07/mouse-models-for-core-binding-factor-leukemia.html
• [Remarks] Stem Cells in the Epithelium of the Stomach
• [Remarks] Cbfb knockout mice
  • URL: http://ircms.kumamoto-u.ac.jp/publications/2015/03/cbfb-knockout-mice.html
• [Remarks] Hematopoietic stem cell enhancer
  • URL: http://ircms.kumamoto-u.ac.jp/publications/2015/01/hematopoietic-stem-cell-enhancer.html