Role of DNA methylation and altered histone modification in development and progression of cancer

2009 Fiscal Year Final Research Report

• Project/Area Number: 17013073
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Sapporo Medical University
• Principal Investigator: TOYOTA Minoru Sapporo Medical University, 医学部, 教授 (70270676)
• Project Period (FY): 2005 – 2009
• Keywords: エピジェネティクス / メチル化 / ヒストン / 遺伝子発現 / クロマチン

Research Abstract

Numerous evidences have suggested that DNA methylation and histone modification play a role in tumorigenesis. However, information about target of epigenetic alterations is not enough. Here, we performed genome wide microarray analysis to identify novel targets of DNA methylation. DNA methylation can also be useful to predict sensitivity of tumors to anti-cancer drugs. We also found that histone H3K4 methylation can be a good molecular marker to identify non-coding RNA silenced by epigenetic changes in cancer.

Research Products

• [Journal Article] IGFBP7 is p53 responsive gene specifically silenced in colorectal cancer with CpG island methylator phenotype. (2010)
  • Author(s): Suzuki H, Igarashi S, Nojima M, Maruyama R, Yamamoto E, Kai M, Akashi H, Watanabe Y, Yamamoto H, Sasaki Y, Itoh F, Imai K, Sugai T, Shen L, Issa JPJ, Shinomura Y, Tokino T, Toyota M.
  • Journal Title: Carcinogenesis 31 Pages: 342-349
  • Peer Reviewed
• [Journal Article] Genomic Screening for Genes Silenced by DNA Methylation Revealed an Association between RASD1 Inactivation and Dexamethasone Resistance in Multiple Myeloma. (2009)
  • Author(s): Nojima M, Maruyama R, Yasui H, Suzuki H, Maruyama Y, Tarasawa I, Sasaki Y, Asaoku H, Sakai H, Hayashi T, Mori M, Imai K, Tokino T, Ishida T, Toyota M, Shinomura Y
  • Journal Title: Clin Cancer Res 15 Pages: 4356-4364
  • Peer Reviewed
• [Journal Article] Cancer Epigenomics: Implications of DNA methylation in personalized therapy. (2009)
  • Author(s): Toyota M, Suzuki H, Yamashita T, Hirata K, Shinomura Y, Tokino T, Imai K
  • Journal Title: Cancer Sci 100 Pages: 787-791
  • Peer Reviewed
• [Journal Article] Overexpression of Aurora a by loss of CHFR gene expresion increases the growth of HTLV-1-infected T cells through enhanced NF-kB activity. (2009)
  • Author(s): Tomita M, Toyota M, Ishikawa C, Nakazato T, Okudaira T, Matsuda T, Uchihara J, Taira N, Ohshiro K, Senba M, Tanaka Y, Ohshima K, Saya H, Tokino T, Mori N
  • Journal Title: Int J Cancer 124 Pages: 2607-2615
  • Peer Reviewed
• [Journal Article] Sensitive and specific detection of early gastric cancer using DNA methylation analysis of gastric washing. (2009)
  • Author(s): Watanabe, Y, Kim, HS, Castoro, RJ, Chyng, W, Estecio, MR, Kondo, K, Guo, Y, Ahmed, SS, Toyota, M, Itoh, F, Suk, KT, Cho, MY, Shen, L, Jelinek, J, Issa, JP.
  • Journal Title: Gastroenterol 136 Pages: 2149-2158
  • Peer Reviewed
• [Journal Article] a potent tumor suppressor (2009)
  • Author(s): Kashima L, Toyota M, Mita H, Suzuki H, Idogawa M, Ogi K, Sasaki Y,, Tokino T. CHFR
  • Journal Title: downregulates interleukin-8 via inhibition of NF-κB. Oncogene 28 Pages: 2643-2653
  • Peer Reviewed
• [Journal Article] Elevated Dnmt3a activity promotes polyposis in ApcMin mice by relaxing extracellular restrains on Wnt signaling. (2009)
  • Author(s): Samuel MS, Suzuki H, Buchert M, Putoczki TL, Tebbutt NC, Lundgren-May T, Christou A, Inglese M, Toyota M, Heath JK, Ward RL, Waring PM, Ernst M
  • Journal Title: Gastroenterol 137 Pages: 902-913
  • Peer Reviewed
• [Journal Article] Characteristic epigenetic profiles of malignant pleural mesothelioma. (2009)
  • Author(s): Goto Y, Shinjo K, Kondo Y, Shen L, Toyota M, Suzuki H, Gao Y, An B, Fujii M, Murakami H, Osada H, Taniguchi T, Usami N, Kondo M, Hasegawa Y, Shimokata K, Matsuo K, Hida T, Fujimoto N, Kishimoto T, Issa JP, Sekido Y
  • Journal Title: Cancer Res 69 Pages: 9073-9082
  • Peer Reviewed
• [Journal Article] Epigenetic silencing of microRNA-34b/c and BTG4 is associated with CpG island methylation in colorectal cancer. (2008)
  • Author(s): Toyota M, Suzuki H, Sasaki Y, Maruyama R, Imai K, Shinomura Y, Tokino T
  • Journal Title: Cancer Res 68 Pages: 4123-4132
  • Peer Reviewed
• [Journal Article] DNA hypermethylation contributes incomplete synthesis of carbohydrate determinants in gastrointestinal cancer. (2008)
  • Author(s): Kawamura YI, Toyota M, Kawashima R, Hagiwara T, Suzuki H, Imai K, Shinomura Y, Tokino T, Kannagi R, Dohi T
  • Journal Title: Gastroenterol 135 Pages: 142-151
  • Peer Reviewed
• [Journal Article] A requirement for DICER to maintain full promoter CpG Island hypermethylation in human cancer cells. (2008)
  • Author(s): Ting A, Suzuki H, Cope L, Schuebel K, Lee B, Toyota M, Imai K, Shinomura Y, Tokino T, Baylin SB
  • Journal Title: Cancer Res 68 Pages: 2570-2575
  • Peer Reviewed
• [Journal Article] dentification of flotillin-2, a major protein on lipid rafths, as a novel target of the p53 family members. (2008)
  • Author(s): Sasaki Y, Ohshima Y, Koyama R, Maruyama R, Akashi H, Mita H, Toyota M, Shinomura Y, Imai K, Tokino T
  • Journal Title: ol Cancer Res 6 Pages: 395-406
  • Peer Reviewed
• [Journal Article] Cytoplasmic RASSF2A is a proapoptotic mediator whose expression is epigenetically silenced in gastric cancer. (2008)
  • Author(s): Maruyama R, Akino K, Toyota M, Suzuki H, Imai T, Ohe-Toyota M, Yamamoto E, Nojima M, Fujikane T, Sasaki Y, Yamashita T, Watanabe Y, Hiratsuka Y, Hirata K, Itoh F, Imai K, Shinomura Y, Tokino T
  • Journal Title: Carcinogenesis 29 Pages: 1312-1318
  • Peer Reviewed
• [Journal Article] The hsitone deacetylase inhibitor FK288 enhances adenovirus- mediated p53 family gene therapy in cancer models. (2008)
  • Author(s): Sasaki Y, Negishi H, Idogawa M, Suzuki H, Mita H, Toyota M, Shinomura Y, Imai K, Tokino T
  • Journal Title: Mol Cancer Ther 7 Pages: 779-787
  • Peer Reviewed
• [Journal Article] LINE-1 hypomethylation is associated with increased CpG island methylation in helicobactor pylori-related enlarged fold gastritis. (2008)
  • Author(s): Yamamoto E, Toyota M, Suzuki H, Kondo Y, Imai K, Sanomura T, Murayama Y, Ohe-Toyota M, Maruyama R, Nojima M, Ashida M, Fujii K, Sasaki Y, Hayashi N, Mori M, Imai K, Tokino T, Shinomura Y
  • Journal Title: Cancer Epidemiol Biomarkers Prev 2555-2564 Pages: 2555-2564
  • Peer Reviewed
• [Journal Article] DNA methylation and cancer pathways in gastrointestinal tumors. (2008)
  • Author(s): Suzuki H, Tokino T, Shinomura Y, Imai K, Toyota M
  • Journal Title: Pharmacogenomics 9 Pages: 1917-1928
  • Peer Reviewed
• [Journal Article] Integrated genetic and epigenetic analysis identifies colon cancer corresponding to three different subclasses of disease. (2007)
  • Author(s): Shen L, Toyota M, Kondo Y, Lin E, Zhang L, Guo Y, Hernandez N, Chen X, Ahmed S, Konishi K, Hamilton SR, Issa JPJ
  • Journal Title: Proc Natl Acad Sci U S A 104
  • Peer Reviewed
• [Journal Article] Gene amplification and overexpression of PRDM14 in breast cancer (2007)
  • Author(s): Nishikawa N, Toyota M, Suzuki H, Homma T, Fujikane T, Ohmura T, Nishidate T, Ohe-Toyota M, Maruyama R, Sonoda T, Sasaki Y, Urano T, Imai K, Hirata K, Tokino T
  • Journal Title: Cancer Res 67 Pages: 9649-9657
  • Peer Reviewed
• [Journal Article] Comparing the DNA hypermethylation with gene mutations in human colorectal cancer. (2007)
  • Author(s): Schuebel KE, Chen E, Cope Lm Glockner SC, Suzuki H, Yi JM, Chan TA, Van Neste L, Van Criekinge W, van den Bosch S, van Engel, M, Ting AH, Jair K, Yu W, Toyota M, Imai K, Ahuja N, Herman JG, Baylin SB
  • Journal Title: Plos Genet 3 Pages: 1709-1723
  • Peer Reviewed
• [Journal Article] Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer. (2007)
  • Author(s): Akino K, Toyota M, Suzuki H, Imai T, Maruyama R, Kusano M, Nishikawa N, Watanabe Y, Sasaki Y, Abe T, Yamamoto E, Tarasawa I, Sonoda T, Mori M, Imai K, Shinomura Y, Tokino T
  • Journal Title: Cancer Sci 98 Pages: 88-95
  • Peer Reviewed
• [Journal Article] Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer. (2007)
  • Author(s): Nojima M, Suzuki H, Toyota M, Watanabe Y, Maruyama R, Sasaki S, Sasaki Y, Mita H, Nishikawa N, Yamaguchi K, Hirata K, Itoh F, Tokino T, Mori M, Imai K, Shinomura Y
  • Journal Title: Oncogene 26 Pages: 4699-4713
  • Peer Reviewed
• [Journal Article] Expression profiling of PRDM family genes identified PRDM5 as a target of epigenetic silencing in colorectal and gastric cancer. (2007)
  • Author(s): Watanabe Y, Toyota M, Kondo Y, Suzuki H, Imai T, Ohe-Toyota M, Maruyama R, Nojima M, Sasaki Y, Sekido Y, Hiratsuka H, Shinomura Y, Imai K, Itoh F, Tokino T
  • Journal Title: Clin Cancer Res 13 Pages: 4786-4794
  • Peer Reviewed
• [Journal Article] Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors. (2007)
  • Author(s): Sato H, Suzuki H, Toyota M, Nojima M, Maruyama R, Sasaki S, Takagi H, Sogabe Y, Sasaki Y, Idogawa M, Sonoda T, Mori M, Imai K, Tokino T, Shinomura Y
  • Journal Title: Carcinogenesis 28 Pages: 2459-2466
  • Peer Reviewed
• [Journal Article] Antitumor effect of adenoviras-mediated p53 family gene transfer on osteosarcoma cell lines. (2007)
  • Author(s): Ohshima Y, Sasaki Y, Negishi H, Idogawa M, Toyota M, Yamashita T, Wada T, Nagoya S, Kawaguchi S, Yamashita T, Tokino T
  • Journal Title: ncer Biol Ther 6 Pages: 1058-1066
  • Peer Reviewed
• [Journal Article] HOXB13 is epigenetically inactivated in human renal cell carcinoma and may be a tumor suppressor gene. (2006)
  • Author(s): Okuda H, Toyota M, Ishida W, Furihata M, Tsuchiya M, Kamada T, Tokino T, Shuin T
  • Journal Title: Oncogene 25 Pages: 1733-1742
  • Peer Reviewed
• [Journal Article] Genetic, epigenetic and clinicopathological features of gastric cancers with CpG island methylator phenotype and an association with Epstein-Barr virus. (2006)
  • Author(s): Kusano M, Toyota M, Suzuki H, Akino K, Aoki F, Fujita M, Hosokawa M, Shinomura Y, Imai K, Tokino T
  • Journal Title: Cancer 106 Pages: 1467-1479
  • Peer Reviewed
• [Journal Article] Comparative genome analysis identified the vitamin D receptor gene as a direct target of p53-mediated transcriptional activation. (2006)
  • Author(s): aruyama R, Aoki F, Toyota M, Sasaki Y, Akashi H, Mita H, Suzuki H, Akino K, Ohe-Toyota M, Maruyama Y, Tatsumi H, Imai K, Shinomura Y, Tokino T
  • Journal Title: Cancer Res 66 Pages: 4574-4583
  • Peer Reviewed
• [Journal Article] Aberrant methylation and silencing of the BNIP3 gene in colorectal and gastric cancer. (2005)
  • Author(s): Murai M, Toyota M, Suzuki H, Satoh A, Akino K, Mita H, Tokino T, Imai K
  • Journal Title: Clin Cancer Res 11 Pages: 1021-1027
  • Peer Reviewed
• [Journal Article] he RAS effector RASSF2 is a novel tumor suppressor in colorectal cancer. (2005)
  • Author(s): Akino K, Toyota M, Suzuki H, Mita H, Sasaki Y, Ohe-Toyota M, Issa JP, Hinoda Y, Imai K, Tokino T
  • Journal Title: Gastroenterol 129 Pages: 156-169
  • Peer Reviewed
• [Journal Article] Upregulation of BNIP3 by 5-aza-2'-deoxycytidine sensitizes pancreatic cancer cells to hypoxia-mediated cell death. (2005)
  • Author(s): Abe T, Toyota M, Suzuki H, Murai M, Akino K, Ueno M, Nojima M, Yawata A, Miyakawa H, Suga T, Ito H, Endo T, Tokino T, Hinoda Y, Imai K
  • Journal Title: J Gastroenterol 40 Pages: 504-510
  • Peer Reviewed
• [Journal Article] Epigenetic changes in solid and hematopoietic tumors. (2005)
  • Author(s): Toyota M, Issa JP
  • Journal Title: Semin. Oncol. 32 Pages: 521-530
  • Peer Reviewed
• [Presentation] CpG island methylator phenotype in colorectal cancer. (2009)
  • Author(s): Toyota M
  • Organizer: The 14th Korean-Japan Cancer Research Workshop
  • Place of Presentation: Kanazawa
  • Year and Date: 20091218-20091219
• [Presentation] Colorectal cancer epigenome and clinical implication. (2009)
  • Author(s): Toyota M, Suzuki H, Yamamoto E, Kamimae S, Nijima M, Shinomura Y, Imai K
  • Organizer: First Guangzhou Symposium of Cancer Epigenetics and Kick-off Meeting of A3 Forsight Program and 973 Project
  • Place of Presentation: Guangzhou, China
  • Year and Date: 20091120-20091122
• [Presentation] Colorectal cancer epigenetics. (2009)
  • Author(s): Toyota M
  • Organizer: 37Th Meeting of International Society for Oncology and Biomarkers. Amsterdam
  • Place of Presentation: Netherlands
  • Year and Date: 20090927-20090930
• [Presentation] The role of epigenetic changes in cancer immunothelapy. (2009)
  • Author(s): Toyota M, Imai K
  • Organizer: US-Japan Workshop on Immunological Molecular Markers in Oncology
  • Place of Presentation: Hawaii, USA
  • Year and Date: 20090323-20090324
• [Presentation] Epigenetic gene silencing and microRNA in human colon cancer. (2008)
  • Author(s): Toyota M, Imai K
  • Organizer: Symposium, 36th Congress of the International Society for Oncodevelopmental Biology and Medicine
  • Place of Presentation: Tokyo
  • Year and Date: 20081005-20081009
• [Presentation] The role of DNA methylation changes in signaling pathway. (2008)
  • Author(s): Toyota M, Imai K
  • Organizer: AACR Special Conference on Cancer Research: Cancer Epigenetics
  • Place of Presentation: Boston, USA
  • Year and Date: 20080328-20080331
• [Presentation] Epigenetic silencing of genes involved in signaling pathway. (2007)
  • Author(s): Toyota M, Suzuki H, Shinomura Y, Tokino T, Imai K
  • Organizer: Symposium, The 7th Joint Conference of the American Association for Cancer Research and the Japanese Cancer Association
  • Place of Presentation: Hawaii, USA
  • Year and Date: 20070121-20070125
• [Presentation] DNA methylation changes in cancer: application to diagnosis and therapy. (2006)
  • Author(s): Toyota M, Suzuki H, Shinomura Y, Imai K
  • Organizer: Symposium, 34th Congress of the International Society for Oncodevelopmental Biology and Medicine
  • Place of Presentation: Pasadena, USA
  • Year and Date: 20060916-20060920
• [Book] Inflammation-related aberrant patterns of DNA methylation: detection and role in epigenetic deregulation of cancer cell transcriptome. Methods in Mol. Biol: Inflammation and cancer.(Edited by Kozlov SV) (2009)
  • Author(s): Suzuki H, Toyota M, Kondo Y, Shinomura Y
  • Total Pages: 55-69
  • Publisher: Humana Press
• [Book] CHFR as a potential anticancer target. (Edited by Dai W, Cancer Drug Discovery and Development Checkpoint Response in Cancer Therapy.) (2008)
  • Author(s): Toyota M, Kashima L, Tokino T
  • Total Pages: 163-176
  • Publisher: Humana Press
• [Book] The role and clinical implication of DNA methylation in gastrointestinal cancer.(Edited by Bamba H and Ota S, Recent Advances in Gastrointestinal Carcinogenesis.) (2006)
  • Author(s): Toyota M, Suzuki H, Maruyama R, Tarasawa I, Yamamoto E, Tokino T, Imai K, Shinomura Y.
  • Total Pages: 115-123
  • Publisher: Transworld Research Network, Kerala
• [Remarks]
  • URL: http://web.sapmed.ac.jp/biochem/
• [Patent(Industrial Property Rights)] 新規遺伝子ACMG1のメチル化を指標とする胃癌の診断方法 (2009)
  • Inventor(s): 豊田実、株式会社ジェネティックラボ
  • Industrial Property Rights Holder: 豊田実、株式会社ジェネティックラボ
  • Industrial Property Number: 特許特許第4426549号
  • Acquisition Date: 2009-12-18
• [Patent(Industrial Property Rights)] 癌の検出方法および検出用キット、ならびに癌治療剤 (2008)
  • Inventor(s): 豊田実
  • Industrial Property Rights Holder: 札幌医科大学
  • Industrial Property Number: 特許特願2008-121671
  • Filing Date: 2008-05-07
• [Patent(Industrial Property Rights)] 乳癌および卵巣癌の治療薬、検出方法ならびに検出用キット (2006)
  • Inventor(s): 豊田実
  • Industrial Property Rights Holder: 札幌医科大学
  • Industrial Property Number: 特許特願2006-263232
  • Acquisition Date: 2006-09-27
• [Patent(Industrial Property Rights)] 胃粘膜洗浄液を利用した疾患関連マーカー検出法 (2006)
  • Inventor(s): 豊田実
  • Industrial Property Rights Holder: 札幌医科大学
  • Industrial Property Number: 特許特願2006-134878
  • Acquisition Date: 2006-05-12