Malignant conversion of epithelial cancers through dysregulation of the p63-MYC pathway

2013 Fiscal Year Final Research Report

• Project/Area Number: 23590375
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: YUGAWA Takashi 独立行政法人国立がん研究センター, 研究所, 主任研究員 (80311372)
• Project Period (FY): 2011 – 2013
• Keywords: 分子腫瘍学 / 癌 / 悪性化 / 幹細胞性 / 発現制御 / p63 / MYC

Research Abstract

Cancer cells evolve from normal cells through multiple genetic alterations. In particular, identification of a genetic cause behind the acquisition of the metastatic ability is very important for elucidating the nature of cancer.
In this study, I have found the possibility that p63, master regulator of epithelial development and stemness maintenance, acts as both an oncogene and tumor suppressor by increasing the proliferative capacity of cells while constraining metastatic tumor progression in early stages of carcinogenesis. I propose, for the first time, that up-regulation of c-MYC oncogene cancels the proliferative defect induced by p63 loss, thereby triggering malignant conversion in late stages of epithelial cancer development.

Research Products

• [Journal Article] ATM regulates Cdt1 stability during the unperturbed S phase to prevent re-replication (2014)
  • Author(s): Iwahori S, Kohmon D, Kobayashi J, Tani Y, Yugawa T, Komatsu K, Kiyono T, Sugimoto N, Fujita M
  • Journal Title: Cell Cycle Volume: 13(3) Pages: 471-481
  • DOI: 10.4161/cc.27274
  • Peer Reviewed
• [Journal Article] Noncanonical NOTCH signaling limits self-renewal of human epithelial and induced pluripotent stem cells through ROCK activation (2013)
  • Author(s): Yugawa T, Nishino K, Ohno S, Nakahara T, Fujita M, Goshima N, Umezawa A, Kiyono T
  • Journal Title: Mol Cell Biol Volume: 33(22) Pages: 4434-4447
  • DOI: 10.1128/MCB.00577-13
  • Peer Reviewed
• [Journal Article] Heterocomplex formation by Arp4 andβ-actin is involved in the integrity of the Brg1 chromatin remodeling complex (2012)
  • Author(s): Nishimoto N, Watanabe M, Watanabe S, Sugimoto N, Yugawa T, Ikura T, Koiwai O, Kiyono T, Fujita M
  • Journal Title: J Cell Sci Volume: 125(Pt 16) Pages: 3870-3882
  • DOI: 10.1242/jcs.104349
  • Peer Reviewed
• [Journal Article] A critical role of MYC for transformation of human cells by HPV16 E6E7 and oncogenic HRAS (2012)
  • Author(s): Narisawa-Saito M, Inagawa Y, Yoshimatsu Y, Haga K, Tanaka K, Egawa N, Ohno S, Ichikawa H, Yugawa T, Fujita M, Kiyono T
  • Journal Title: Carcinogenesis Volume: 33(4) Pages: 910-917
  • DOI: 10.1093/carcin/bgs104
  • Peer Reviewed
• [Journal Article] The E1 protein of human papillomavirus type 16 is dispensable for maintenance replication of the viral genome (2012)
  • Author(s): Egawa N, Nakahara T, Ohno S, Narisawa-Saito M, Yugawa T, Fujita M, Yamato K, Natori Y, Kiyono T
  • Journal Title: J Virol Volume: 86(6) Pages: 3276-3283
  • DOI: 10.1128/JVI.06450-11
  • Peer Reviewed
• [Journal Article] An in vitro multistep carcinogenesis model for both HPV-positive and -negative human oral squamous cell carcinomas (2011)
  • Author(s): Zushi Y, Narisawa-Saito M, Noguchi K, Yoshimatsu Y, Yugawa T, Egawa N, Fujita M, Urade M, Kiyono T
  • Journal Title: Am J Cancer Res Volume: 1(7) Pages: 869-881
  • URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3196285/
  • Peer Reviewed
• [Journal Article] Chromatin remodeler sucrose nonfermenting 2 homolog (SNF2H) is recruited onto DNA replication origins through interaction with Cdc10 protein-dependent transcript 1 (Cdt1) and promotes pre-replication complex formation (2011)
  • Author(s): Sugimoto N, Yugawa T, Iizuka M, Kiyono T, Fujita M
  • Journal Title: J Biol Chem Volume: 286(45) Pages: 39200-39210
  • DOI: 10.1074/jbc.M111.256123
  • Peer Reviewed
• [Presentation] Non-canonical NOTCH signaling limits self-renewal of human keratinocytes through ROCK activation.(非古典的NOTCHシグナルはROCKの活性化を介して角化細胞の自己複製能を制限する) (2013)
  • Author(s): 温川恭至, 大野真一, 中原知美, 藤田雅俊, 五島直樹, 清野透
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸(示説発表)
  • Year and Date: 2013-12-04
• [Presentation] Non-canonical NOTCH signaling integrates into ROCK activation to induce differentiation of human keratinocytes.(非古典的NOTCHシグナリングによるROCKの活性化と角化細胞分化) (2013)
  • Author(s): 温川恭至, 大野真一, 中原知美, 藤田雅俊, 五島直樹, 清野透
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜(口演)
  • Year and Date: 2013-10-05
• [Presentation] Molecular mechanisms dictating the biological outcome of p63 loss in human keratinocytes (2013)
  • Author(s): Yugawa T, Kiyono T
  • Organizer: The 6th International p63/p73 Workshop
  • Place of Presentation: Kazusa Akademia Park
  • Year and Date: 2013-09-17
  • Invited
• [Presentation] Dysregulation of the p63-MYC pathway in the development of squamous cell carcinomas.(扁平上皮がん発生におけるp63-MYC経路の異常) (2012)
  • Author(s): 温川恭至, 藤田雅俊, 清野透
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌(口演)
  • Year and Date: 2012-09-19
• [Presentation] -MYC over-expression cancels the proliferative defect triggered by p63 loss in keratinocytes.(c-MYCの過剰発現はp63欠損による角化細胞増殖能の喪失を回避する) (2011)
  • Author(s): 温川恭至, 藤田雅俊, 清野透
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋(示設発表)
  • Year and Date: 2011-10-03
• [Presentation] Regulation of Notch1 gene expression by p53 family members and its disruption by HPV-16 E6 (2011)
  • Author(s): Yugawa T, Kiyono T
  • Organizer: ICGEB (International Centre for Genetic Engineering and Biotechnology) DNA Tumour Virus Meeting
  • Place of Presentation: Trieste, Italy(口演)
  • Year and Date: 2011-07-23
• [Remarks]
  • URL: http://www.ncc.go.jp/jp/nccri/divisions/10vir/10vir.html