Creation of novel diagnostic methods and epigenome therapy based on higher-order epigenome analysis in treatment-resistant oral cancer

• Project/Area Number: 16K20595
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Surgical dentistry
• Research Institution: Kumamoto University
• Principal Investigator: Hirosue Akiyuki 熊本大学, 医学部附属病院, 助教 (00638182)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 口腔癌 / 治療抵抗性 / 高次エピゲノム / DNAメチル化 / ヒストン修飾 / エピゲノム治療 / エピゲノム / 放射線耐性 / 高悪性 / 高転移

Outline of Final Research Achievements

Oral squamous cell carcinoma (OSCC) has been increased morbidity, and its high malignant potential, including metastasis and therapeutic resistance affects patient survival. Herein, we investigated the higher-order epigemomic alteration in therapeutic resistance of OSCC to develop the novel diagnostic methods and epigenome therapy based on epigenome profile. Bromodomain containing 4 (BRD4) associates with acetylated chromatin and facilitates transcriptional activation. BET inhibitor JQ1 suppressed cell proliferation, migration and invasion in OSCC cell lines, and JQ1 reduced expression levels of matrix metalloproteinase 2 (MMP2), which are associated with cancer metastasis. These results suggest that BRD4 may be a novel therapeutic target in OSCC.

Research Products

• [Journal Article] Tumor budding as a novel predictor of occult metastasis in cT2N0 tongue squamous cell carcinoma (2018)
  • Author(s): Sakata Junki、Yamana Keisuke、Yoshida Ryoji、Matsuoka Yuichiro、Kawahara Kenta、Arita Hidetaka、Nakashima Hikaru、Nagata Masashi、Hirosue Akiyuki、Kawaguchi Sho、Gohara Shunsuke、Nagao Yuka、Hiraki Akimitsu、Shinohara Masanori、Toya Ryo、Murakami Ryuji、Nakayama Hideki
  • Journal Title: Human Pathology Volume: 76 Pages: 1-8
  • DOI: 10.1016/j.humpath.2017.12.021
  • Peer Reviewed / Open Access
• [Journal Article] Severe interstitial pneumonia associated with anti-PD-1 immune checkpoint antibody after talc slurry pleurodesis (2018)
  • Author(s): Sakata Shinya、Matsuoka Yuichiro、Kawahara Kenta、Kakiuchi Yosuke、Takaki Akira、Hirosue Akiyuki、Yoshida Ryoji、Saeki Sho、Fujii Kazuhiko、Nakayama Hideki
  • Journal Title: Respiratory Investigation Volume: 56 Issue: 2 Pages: 195-198
  • DOI: 10.1016/j.resinv.2017.11.006
  • Peer Reviewed / Open Access
• [Journal Article] FBXW7 expression affects the response to chemoradiotherapy and overall survival among patients with oral squamous cell carcinoma: A single-center retrospective study. (2017)
  • Author(s): Hidetaka Arita, Masashi Nagata, Ryoji Yoshida, Yuichiro Matsuoka1, Akiyuki Hirosue, Kenta Kawahara, Junki Sakata, Hikaru Nakashima, Taku Kojima, Ryo Toya, Ryuji Murakami, Akimitsu Hiraki, Masanori Shinohara and Hideki Nakayama.
  • Journal Title: Tumour Biology Volume: 39 Issue: 10 Pages: 1-9
  • DOI: 10.1177/1010428317731771
  • Peer Reviewed / Open Access
• [Journal Article] Salivary duct carcinoma treated with cetuximab-based targeted therapy: A case report. (2017)
  • Author(s): Kawahara K, Hiraki A, Yoshida R, Arita H, Matsuoka Y, Yamashita T, Koga K, Nagata M, Hirosue A, Fukuma D, Nakayama H.
  • Journal Title: Molecular and clinical oncology Volume: 6 Issue: 6 Pages: 886-892
  • DOI: 10.3892/mco.2017.1226
  • Peer Reviewed
• [Journal Article] The glucocorticoid receptor regulates the ANGPTL4 gene in a CTCF-mediated chromatin context in human hepatic cells. (2017)
  • Author(s): Nakamoto M, Ishihara K, Watanabe T, Hirosue A, Hino S, Shinohara M, Nakayama H, and Nakao M
  • Journal Title: PLOS ONE Volume: 12
  • Peer Reviewed / Open Access
• [Journal Article] Predictive value of the combination of SMAD4 expression and lymphocyte infiltration in malignant transformation of oral leukoplakia. (2017)
  • Author(s): Sakata J, Yoshida R, Matsuoka Y, Nagata M, Hirosue A, Kawahara K, Nakamura T, Nakamoto M, Hirayama M, Takahashi N, Nakashima H, Arita H, Ogi H, Hiraki A, Shinohara M, Nakayama H
  • Journal Title: Cancer medicine Volume: 6 Issue: 4 Pages: 730-738
  • DOI: 10.1002/cam4.1005
  • Peer Reviewed / Open Access
• [Journal Article] IL-6 controls resistance to radiation by suppressing oxidative stress via the Nrf2-antioxidant pathway in oral squamous cell carcinoma. (2016)
  • Author(s): Matsuoka Yuichiro
  • Journal Title: Br J Cancer Volume: 115 Issue: 10 Pages: 1234-1244
  • DOI: 10.1038/bjc.2016.327
  • Peer Reviewed
• [Journal Article] Factors affecting volume change of myocutaneous flaps in oral cancer. (2016)
  • Author(s): Hiraki Akimitsu
  • Journal Title: Int J Oral Maxillofac Surg Volume: 45 Issue: 11 Pages: 1395-1399
  • DOI: 10.1016/j.ijom.2016.04.014
  • Peer Reviewed
• [Presentation] BRD4はMMP2遺伝子座にエピジェネティックな調節を介して口腔扁平上皮癌の転移に関与する (2018)
  • Author(s): 山本 達郎、廣末 晃之、中元 雅史、川原 健太、高橋 望、吉田 遼司、平木 昭光、篠原 正徳斉藤 典子、中尾 光善、中山 秀樹
  • Organizer: 第36回 日本口腔腫瘍学会総会・学術大会
• [Presentation] Overexpression of IGFBP3 contributes to radioresistance and a poor prognosis in oral squamous cell carcinoma (2017)
  • Author(s): Junki Sakata, Akiyuki Hirosue, Ryoji Yoshida, Yuichiro Matsuoka, Kenta Kawahara, Tatsuro Yamamoto, Hidetaka Arita, Hikaru Nakashima, Shunsuke Gohara, Sho Kawaguchi, Yuka Nagao, Keisuke Yamana, Hideki Nakayama
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] IGFBP3 は DNA 修復の促進を介して口腔扁平上皮癌に放射線抵抗性を附与する (2017)
  • Author(s): 坂田純基、廣末晃之、吉田遼司、松岡祐一郎、永田将士、川原健太、高橋望、有田英生、中嶋光、田中拓也、福間大喜、尾木秀直、中山秀樹
  • Organizer: 第41回日本頭頸部癌学会
• [Presentation] IGFBP3 は DNA 修復の促進を介して口腔扁平上皮癌に放射線抵抗性を附与する (2017)
  • Author(s): 坂田純基、廣末晃之、吉田遼司、松岡祐一郎、永田将士、川原健太、有田英生、中嶋光、田中拓也、福間大喜、尾木秀直、中山秀樹
  • Organizer: 第71回NPO法人日本口腔科学会学術集会
• [Presentation] The clinicopathological analysis of IGFBP3 in oral squamous cell carcinoma. (2016)
  • Author(s): 坂田 純基、廣末 晃之、吉田 遼司、永田 将士、松岡 祐一郎、有田 英生、中嶋 光、 川原 健太、福間 大喜、尾木 秀直、篠原 正徳、中山 秀樹
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜、神奈川
  • Year and Date: 2016-10-06
• [Presentation] BRD4 contributes to metastasis in oral squamous cell carcinoma through the epigenetic regulation of MMP2. (2016)
  • Author(s): 山本達郎、廣末晃之、中元雅史、吉田遼司、川原健太、永田将士、田中拓也、斉藤典子、中尾光善、中山秀樹
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜、神奈川
  • Year and Date: 2016-10-06
• [Presentation] 口腔扁平上皮癌におけるHMGA2の臨床的意義 (2016)
  • Author(s): 坂田純基, 廣末晃之, 吉田遼司, 永田将士, 松岡祐一郎, 有田英生, 中嶋光, 福間大喜, 尾木秀直, 篠原正徳, 中山秀樹
  • Organizer: 第40回日本頭頸部癌学会
  • Place of Presentation: 大宮ソニックシティ、埼玉
  • Year and Date: 2016-06-09