Higher-order epigenetic analysis of the INK4/ARF locus in oral cancer and development of novel diagnostic methods

• Project/Area Number: 24890176
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Surgical dentistry
• Research Institution: Kumamoto University
• Principal Investigator: HIROSUE Akiyuki 熊本大学, 医学部附属病院, 医員 (00638182)
• Project Period (FY): 2012-08-31 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: INK4/ARF遺伝子座 / 高次エピゲノム / DNAメチル化 / 口腔扁平上皮癌 / 薬剤耐性 / エピジェネティクス / クロマチン高次構造 / INK4/ARF 遺伝子座

Research Abstract

Three critical tumor suppressors (p15/ARF /p16) encoded by the INK4/ARF locus are key regulators of tumorigenesis. In this study, to elucidate a higher-ordered epigenetic regulation of the locus in oral squamous cell carcinoma (OSCC) and to develop novel diagnostic methods based on epigenetic profile, we investigated the relevance between clinical effect and epigenetic alterations inOSCC. Chromosome conformation capture assay revealed that higher-order chromatin structure of the INK4/ARF locus dynamically changed in OSCC cell line. DNA methylation analysis demonstrated that hypermethylation of MGMT and TFAP2E genes were associated with pathological response to 5-FU-based chemoradiotherapy. These results suggest that methylation status of these genes may provide the prediction of drug sensitivity in OSCC.

Research Products

• [Journal Article] A low dicer expression is associated with resistance to 5-FU-based chemoradiotherapy and a shorter overall survival in patients with oral squamous cell carcinoma (2014)
  • Author(s): Kawahara K, Nakayama H, Nagata M, Yoshida R, Hirosue A, Tanaka T, Nakagawa Y, Matsuoka Y, Kojima Taku, Takamune Y, Yoshitake Y, Hiraki A, Shinohara M
  • Journal Title: J Oral Pathol Med Volume: 43 Pages: 350-356
  • Peer Reviewed
• [Journal Article] Overexpression of fibronectin confers cell adhesion-mediated drug resistance (CAM-DR) against 5-FU in oral squamous cell carcinoma cells (2014)
  • Author(s): Nakagawa Y, Nakayama H, Nagata M, Yoshida R, Hirosue A, Tanaka T, Kawahara K, Matsuoka Y, Kojima Taku, Takamune Y, Yoshitake Y, Hiraki A, Shinohara M
  • Journal Title: Int J Oncol Volume: 44 Pages: 1376-1384
  • Peer Reviewed
• [Presentation] Epigenetic analysis of the drug resistance in oral squamous cell carcinoma (2013)
  • Author(s): Nakamoto M,Hirosue A,Nakamura C,Kawahara K,Nakagawa Y,Yoshida R,Nagata M,Nakayama H,Hiraki A,Shinohara
  • Organizer: 21ST INTERNATIONAL CONFERENCE ON ORAL AND MAXILLOFACIAL SURGERY
  • Place of Presentation: Palaude Congressos, Barcelona, Spain
• [Presentation] 口腔扁平上皮癌の抗癌剤耐性に関与するエピケノム異常 (2013)
  • Author(s): 廣末晃之、中山秀樹、中元雅史、中村智穂、川原健太、中川純泰、吉田遼司、永田将士、平木昭光、牧正啓、篠原正徳
  • Organizer: 第58回日本口腔外科学会総会学術大会
  • Place of Presentation: 福岡国際会議場福岡
• [Presentation] Epigenetic alterations in the drug resistance of oral squamous cell carcinoma (2013)
  • Author(s): Hirosue A,Nakamoto M,Nakamura C,Kawahara K,Nakagawa Y,Yoshida R,Nagata M,Nakayama H,Hiraki A,Shinohara M
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフイコ横浜神奈川
• [Presentation] Epigenetic alterations in the drug resistance of oral squamous cell carcinoma. (2013)
  • Author(s): Akiyuki Hirosue, Masafumi Nakamoto, Chiho Nakamura, Kenta Kawahara, Nakagawa Yoshihiro, Ryoji Yoshida, Masashi Nagata, Hideki Nakayama, Akimitsu Hiraki, Masanori Shinohara
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] 口腔扁平上皮癌の抗癌剤耐性に関与するエピゲノム異常 (2013)
  • Author(s): 廣末 晃之、中山 秀樹、中元 雅史、中村 智穂、川原 健太、中川 純泰、吉田 遼司、永田 将士、平木 昭光、牧 正啓、篠原 正徳
  • Organizer: 第58回日本口腔外科学会総会・学術大会
  • Place of Presentation: 福岡国際会議場
• [Presentation] Epigenetic analysis of the drug resistance in oral squamous cell carcinoma (2013)
  • Author(s): Masafumi Nakamoto, Akiyuki Hirosue, Chiho Nakamura, Kenta Kawahara, Nakagawa Yoshihiro, Ryoji Yoshida, Masashi Nagata, Hideki Nakayama, Akimitsu Hiraki, Masanori Shinohara
  • Organizer: 21ST INTERNATIONAL CONFERENCE ON ORAL AND MAXILLOFACIAL SURGERY
  • Place of Presentation: Palau de Congressos, Barcelona, Spain
• [Presentation] Quantitative assessment of higher-order chiromatin structure of the INK4/ARF locus in reprogrammed human cells (2012)
  • Author(s): Hirosue A, Nakayama H, Ishihara K, Nakamoto M, Nagata M, Kawahara K, Yoshida R, Nakao M, Shinohara M
  • Organizer: 17th World Congress on Advances in Oncology and 15th International Symposium on Molecular Medicine
  • Place of Presentation: Hotel Creta Maris Resort, Creta, Greece
• [Presentation] Quantitative assessment of higher-order chiromatin structure of the INK4/ARF locus in human senescent cells (2012)
  • Author(s): Hirosue A, Nakamoto M, shihara K, Takehisa T, Narita M, Nakao M, Shinohara M
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌北海道
• [Presentation] Quantitative assessment of higher-order chiromatin structure of the INK4/ARF locus in human senescent cells (2012)
  • Author(s): Akiyuki HIrosue
  • Organizer: 第71回 日本癌学会学術総会
  • Place of Presentation: ロイトン札幌、 北海道 札幌
• [Presentation] Quantitative assessment of higher-order chiromatin structure of the INK4/ARF locus in reprogrammed human cells (2012)
  • Author(s): Akiyuki HIrosue
  • Organizer: 17th World Congress on Advances in Oncology and15th International Symposium on Molecular Medicine
  • Place of Presentation: Hotel Creta Maris Resort, Creta-Greece