Development of DNA demethylation technology in cancer cells and its application for discovering biomarkers for early diagnosis

• Project/Area Number: 24590471
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Tohoku University
• Principal Investigator: FUKUSHIGE Shinichi 東北大学, 医学(系)研究科(研究院), 准教授 (90192723)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 腫瘍 / DNAメチル化 / DNA脱メチル化 / 癌 / ゲノム / 遺伝子 / 発現制御 / 脱メチル化 / 転写活性化

Outline of Final Research Achievements

We have developed a novel method that globally demethylates and reactivates hypermethylated genes by using a fusion gene comprising of methyl-CpG binding domain (MBD) and the catalytic domain of Ten-eleven translocation protein 1 (TET1-CD). This method is useful for identifying hypermethylation-mediated silenced genes in cancer cells. We have applied it to prostate and colorectal cancer cell lines and found that DNA demethylation suppressed the growth of cancer cells. These results suggest that DNA methylation confers the ability of cancer cells to facilitate the growth and DNA methylation of gene(s) responsible for cell growth may be useful as a biomarker.

Research Products

• [Journal Article] S100A4 is frequently overexpressed in lung cancer cells and promotes cell growth and cell motility. (2014)
  • Author(s): Chen N, Sato D, Saiki Y, Sunamura M, Fukushige S, Horii A.
  • Journal Title: Biochem Biophys Res Commun Volume: in press Issue: 3 Pages: 459-464
  • DOI: 10.1016/j.bbrc.2014.04.025
  • Peer Reviewed
• [Journal Article] Suppressed expression of NDRG2 correlates with poor prognosis in pancreatic cancer (2013)
  • Author(s): Yamamura A, et al
  • Journal Title: Biochem Biophys Res Commun Volume: 441(1) Issue: 1 Pages: 102-7
  • DOI: 10.1016/j.bbrc.2013.10.010
  • Peer Reviewed
• [Journal Article] DNA Methylation in Cancer: A Gene Silencing Mechanism and the Clinical Potential of Its Biomarkers (2013)
  • Author(s): Fukushige S, Horii A.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 229 Issue: 3 Pages: 173-185
  • DOI: 10.1620/tjem.229.173
  • NAID: 10031161717
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed
• [Journal Article] Road to early detection of pancreatic cancer : Attempts to utilize epigenetic biomarkers (2012)
  • Author(s): Shinichi Fukushige
  • Journal Title: Cancer Lett Volume: (未定)(in press) Issue: 2 Pages: 231-237
  • DOI: 10.1016/j.canlet.2012.03.022
  • Peer Reviewed
• [Journal Article] S100A4, frequently overexpressed in various human cancers, accelerates cell motility in pancreatic cancercells (2012)
  • Author(s): Sekine H, Chen N, Sato K, Saiki Y, Yoshino Y, Umetsu Y, Jin G, Nagase H, Gu Z, Fukushige S, Sunamura M, Horii A.
  • Journal Title: Biochem Biophys Res Commun Volume: 429 Issue: 3-4 Pages: 214-219
  • DOI: 10.1016/j.bbrc.2012.10.048
  • Peer Reviewed
• [Journal Article] miR-34a is downregulated in cis-diamminedichloroplatinum treated sinonasal squamous cell carcinoma patients with poor prognosis. (2012)
  • Author(s): Takenori Ogawa
  • Journal Title: Cancer Sci Volume: 103 Pages: 1737-1743
  • Peer Reviewed
• [Journal Article] DCK is frequently inactivated in acquired gemcitabine-resistant human cancer cells (2012)
  • Author(s): Yuriko Saiki
  • Journal Title: Biochemical and Biophysical Research Communications Volume: (in press) Issue: 1 Pages: 98-104
  • DOI: 10.1016/j.bbrc.2012.03.122
  • Peer Reviewed
• [Presentation] Methyl-CpG targeted DNA demethylation by TET hydroxylase activity suppresses the growth of cancer cells. (2014)
  • Author(s): 福重 真一、齋木 由利子、堀井 明
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] S100A4 is frequently overexpressed in lung cancer cells and promotes cell motility. (2014)
  • Author(s): 陳 娜、齋木 由利子、砂村 真琴、福重 真一、堀井 明
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] TET oxidase activity accumulated on methyl-CpG sites extensively upregulates methylated genes through DNA demethylation. (2014)
  • Author(s): Fukushige S, Mizuguchi Y, Horii A
  • Organizer: 105th American Association for Cancer Research Annual Meeting
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] IFI27 and NOV, downstream regulated genes by S100A4, are playing important roles in pancreatic carcinogenesis. (2014)
  • Author(s): Chen N, Saiki Y, Sekine H, Sunamura M, Fukushige S, Motoi F, Egawa S, Unno M, Hroii A
  • Organizer: 105th American Association for Cancer Research Annual Meeting
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] MeTA-array, a useful method to identify genes transcriptionally silenced by tumor-specific hypermethylation in cancer. (2013)
  • Author(s): Fukushige S, Horii A
  • Organizer: 104th American Association for Cancer Research Annual Meeting
  • Place of Presentation: Washington DC, USA
• [Presentation] TET1蛋白のヒドロキシラーゼ活性はエピジェネティックに転写抑制された遺伝子の再活性化を引き起こす (2013)
  • Author(s): 福重真一、水口康彦、堀井明
  • Organizer: 第72回 日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] S100A4の下流で制御されるIFI27、NOVの膵癌の発生、進展における役割の解析 (2013)
  • Author(s): 陳娜、齋木由利子、砂村真琴、福重真一、元井冬彦、江川新一、海野倫明、堀井明
  • Organizer: 第72回 日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] MeTA-array, a useful method to identify genes transcriptionally silenced by tumor-specific hypermethylation in cancer. (2013)
  • Author(s): Shinichi Fukushige
  • Organizer: American Association for Cancer Research Annual Meeting 2013
  • Place of Presentation: Washington DC, USA
• [Presentation] ヒト癌において腫瘍特異的な高度メチル化により転写抑制された遺伝子のMeTA-arrayによる効率的探索法の開発 (2012)
  • Author(s): 福重真一
  • Organizer: 第７１回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] ゲムシタビン耐性ヒト癌細胞株におけるdeoxycytidine kinaseの不活化 (2012)
  • Author(s): 齋木由利子
  • Organizer: 第７１回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] miR-34a発現低下は鼻副鼻腔癌におけるシスプラチン化学療法の予後規定因子である (2012)
  • Author(s): 小川武則
  • Organizer: 第７１回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Book] Biomarkers in Cancer. (2015)
  • Author(s): Fukushige S, Horii A.
  • Publisher: Springer
• [Remarks] 東北大学大学院医学系研究科病理学講座分子病理学分野
  • URL: http://www.molpath.med.tohoku.ac.jp/index.html
• [Remarks] 東北大学医学部 分子病理学分野
  • URL: http://www.med.tohoku.ac.jp/org/medical/13/index.html
• [Remarks] 東北大学医学部 分子病理学分野
  • URL: http://www.med.tohoku.ac.jp/org/medical/13/index.html