Screening of polycomb Bmi1 targets for development of Cancer Stem Cell-targeted therapy for neuroblastoma

2011 Fiscal Year Final Research Report

• Project/Area Number: 21591377
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: KAMIJO Takehiko 千葉県がんセンター(研究所), 発がん研究グループ, 部長 (90262708)
• Project Period (FY): 2009 – 2011
• Keywords: Bmi1 / 小児腫瘍 / ポリコーム / がん幹細胞

Research Abstract

We clarified the direct binding of MYCN to Bmi1 promoter and upregulation of Bmi1 transcription by MYCN. A correlation between MYCN and polycomb protein Bmi1 expression was observed in primary NB tumors. Expression of Bmi1 resulted in the acceleration of proliferation and colony formation in NB cells. Bmi1-related inhibition of NB cell differentiation was confirmed by neurite extension assay and analysis of differentiation marker molecules. Intriguingly, the above-mentioned Bmi1-related regulation of the NB cell phenotype seems not to be mediated only by p14ARF/p16INK4a in NB cells. Expression profiling analysis using a tumor-specific cDNA microarray addressed the Bmi1-dependent repression of KIF1Bb and TSLC1, which have important roles in predicting the prognosis of NB. Chromatin immunoprecipitation assay showed that KIF1Bb and TSLC1 are direct targets of Bmi1 in NB cells.
Further comprehensive molecular analysis indicated that RUNX3 appears to be a target of Bmi1 and its transcription was suppressed by Bmi1 in several malignancies, including neuroblastoma.
Analysis of the molecular mechanism of Bmi1-knockdown-induced apoptosis clarified that DNA damage induced by Bmi1 knockdown has an important role. This apoptosis is dependent on p53 and/or p73 and accompanied by production of reactive oxygen species. Furthermore, we studied the role of the other polycomb group molecules in the Bmi1-knockdown-induced apoptotic cell death.

Research Products

• [Journal Article] CD133 suppresses neuroblastoma cell differentiation via signal pathway-modification (2011)
  • Author(s): Takenobu H, Shimozato O, Nakamura T, Ochiai H, Yamaguchi Y, Ohira M, Nakagawara A, Kamijo T
  • Journal Title: ONCOGENE Volume: 30(1) Pages: 97-105
• [Journal Article] Mammalian Polycomblike Pcl2/Mtf2 is a novel regulatory component of PRC2 that can differentially modulate Polycomb activity at both the Hox gene cluster and at Cdkn2a genes (2011)
  • Author(s): Li X, Isono K, Yamada D, Endo TA, Endoh M, Shinga J, Koseki YM, Otte AP, Casanova M, Kitamura M, Kamijo T, Sharif J, Ohara O, Toyada T, Bernstein BE, Brockdorff N and Koseki H
  • Journal Title: Mol Cell Biol Volume: 31(2) Pages: 351-64
• [Journal Article] Bmi1 regulates cell fate via tumor suppressor WWOX repression in small cell lung cancer cells (2011)
  • Author(s): Kimura M, Takenobu H, Akita N, Nakazawa A, Ochiai H, Shimozato O, Fujimura YI, Koseki H, Yoshino I, Kimura H, Nakagawara A, Kamijo T
  • Journal Title: Cancer Sci Volume: 102(5) Pages: 983-990
• [Journal Article] Regulation of the MDM2-P53 Pathway and Tumor Growth by PICT1/GLTSCR2 via Nucleolar RPL11 (2011)
  • Author(s): Sasaki M, Kawahara K, Nishio M, Mimori K, Kogo R, Hamada K, Itoh B, Wang J, Komatsu Y, Yang YR, Hikasa H, Horie Y, Yamashita T, Kamijo T, Zhang Y, Zhu Y, Prives C, Nakano T, Mak TW, Sasaki T, Tomohiko Maehama T, Mori M, and Suzuki A
  • Journal Title: Nat Med Volume: 17(8) Pages: 944-51
• [Journal Article] Bmi1 is a MYCN target gene and regulates tumorigenesis via repression of KIF1B・and TSLC1 in neuroblastoma (2010)
  • Author(s): Ochiai H, Takenobu H, Nakagawa A, Yamaguchi Y, Kimura K, Ohira M, Okimoto Y, Fujimura Y, Koseki H, Kohno Y, Nakagawara A, Kamijo T
  • Journal Title: ONCOGENE Volume: 29(18) Pages: 2681-90
• [Journal Article] Polycomb group molecule PHC3 regulates polycomb complex composition and prognosis of osteosarcoma (2010)
  • Author(s): Iwata S, Takenobu H, Kageyama H, Koseki H, Ishii T, Nakazawa A, Tatezaki SI, Nakagawara A, Kamijo T
  • Journal Title: Cancer Sci Volume: 101(7) Pages: 1646-52
• [Journal Article] HDM2 impairs Noxa transcription and affects apoptotic cell death in a p53/p73-dependent manner in neuroblastoma (2010)
  • Author(s): Shi Y, Taenobu H, Kurata K, Yamaguchi Y, Yanagisawa R, Ohira M, Koike K, Nakagawara A, Jiang LL, Kamijo T
  • Journal Title: European J of Cancer Volume: 46(12) Pages: 2324-34
• [Journal Article] Reevaluation of trkA expression as a biological marker of neuroblastoma by high-sensitivity expression analysis-a study of 106 primary neuroblastomas treated in a single institute (2010)
  • Author(s): Hishiki T, Saito T, Terui K, Sato Y, Takenouchi A, Yahata E, Ono S, Nakagawara A, Kamijo T, Nakamura Y, Matsunaga T, Yoshida H
  • Journal Title: J Pediatr Surg Volume: 45(12) Pages: 2293-8
• [Journal Article] Plk1 regulates liver tumor cell death by phosphorylation of TAp63 (2009)
  • Author(s): Komatsu S, Takenobu H, Ozaki T, Ando K, Koida N, Suenaga Y, Ichikawa T, Hishiki T, Chiba T, Iwama A, Yoshida H, Ohnuma N, Nakagawara A, Kamijo T
  • Journal Title: Oncogene Volume: 28(41) Pages: 3631-41
• [Journal Article] TBP(TATA-binding Protein)-like Protein(TLP) Is Engaged in Etoposide-induced Apoptosis Through Transcriptional Activation of HumanTAp63 Gene (2009)
  • Author(s): Suenaga Y, Ozaki T, Tanaka Y, Bu Y, Kamijo T, Tokuhisa T, Nakagawara A, Tamura TA
  • Journal Title: J Biol Chem Volume: 284(51) Pages: 35433-40
• [Book] がん組織バンクとその応用研究 (2010)
  • Author(s): 上條岳彦、中村洋子、大平美紀、中川原章
  • Total Pages: 130-132
  • Publisher: 永井書店
• [Book] 血液・腫瘍性疾患神経芽腫 (2009)
  • Author(s): 上條岳彦
  • Total Pages: 1220-1224
  • Publisher: 東京医学社
• [Remarks]
  • URL: http://www.chiba-cc.jp/inst/jp/organization/005.html