HDAC inhibitors suppress proliferation, migration and invasion of human head and neck squamous cell carcinoma cells via p63-mediated tight junction molecules and p21-mediated growth arrest

• Project/Area Number: 17K16931
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Otorhinolaryngology
• Research Institution: Sapporo Medical University
• Principal Investigator: Kazufumi Obata 札幌医科大学, 医学部, 助教 (00548703)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 頭頸部扁平上皮癌 / HDAC阻害剤 / JAM-A / claudin-1 / p63 / 悪性化 / 癌 / 細胞・組織 / シグナル伝達

Outline of Final Research Achievements

To investigate how histone deacetylase (HDAC) inhibitors affect human head and neck squamous cell carcinoma (HNSCC), HNSCC cell line Detroit 562 and primary cultured HNSCC were treated with HDAC inhibitors.
In the present study, higher expression of p63, HDAC1, JAM-A and claudin-1 was found in the HNSCC regions than in the adjacent dysplastic regions. In the Detroit 562, treatment with the HDAC inhibitor trichostatin A (TSA), downregulated expression of p63, JAM-A and claudin-1. In addition, treatment with TSA suppressed cancer cell proliferation via G2/M arrest, with upregulation of p21 and downregulation of cyclin D1. Treatment with TSA downregulated expression of EGFR and phospho-ERK1/2. In primary cultured HNSCC cells, HDAC inhibitors suppressed the proliferation, migration and invasion of HNSCC via downregulation of the p63-mediated tight junction molecules JAM-A and claudin-1, and induction of p63 or p21-mediated growth arrest.

Academic Significance and Societal Importance of the Research Achievements

頭頸部扁平上皮癌は一般的に予後不良である。癌の浸潤・転移を亢進させる因子であるタイト結合関連分子JAM-A と、ヒストン脱アセチル化酵素（Histone Deacetylase：HDAC）が頭頸部扁平上皮癌で高発現していると報告されている。HDAC阻害剤の抗腫瘍効果が最近報告されているが、その作用メカニズムは不明である。
今回の研究の結果、HDAC阻害剤が頭頸部扁平上皮癌のp63の発現低下を起こし、JAM-A, claudin-1といったタイト結合分子の発現を低下をさせ、癌細胞の浸潤遊走を抑制していると考えられた。
HDAC阻害剤の作用機序解明により、頭頸部扁平上皮癌治療がさらに進むと考えられる。

Research Products

• [Presentation] Evaluation of soluble JAM-A as a biomarker in head and neck squamous cell carcinoma (2018)
  • Author(s): Kazufumi Obata, Takuya Kakuki, Akito Kakiuchi, Makoto Kurose, Atsushi Kondo, Kenichi Takano, Kazuaki Nomura, Ryo Miyata, Takashi Kojima
  • Organizer: 6th world congress of the international federation of head and neck oncologic societies
• [Presentation] 頭頸部扁平上皮癌におけるヒストン脱アセチル化酵素(HDAC)阻害剤のp63依存性タイト結合分子を介した抗腫瘍効果 (2017)
  • Author(s): 垣内晃人、角木拓也、黒瀬誠、高野賢一、近藤敦、小幡和史、野村一顕、宮田亮、金子躍人、幸野貴之、氷見徹夫、小島隆
  • Organizer: 第68回日本細胞生物学会
• [Presentation] 頭頸部扁平上皮癌におけるヒストン脱アセチル化酵素(HDAC)阻害剤のp63依存性タイト結合分子を介した抗腫瘍効果 (2017)
  • Author(s): 垣内晃人、角木拓也、黒瀬誠、高野賢一、近藤敦、小幡和史、野村一顕、宮田遼、金子躍人、氷見徹夫、小島隆
  • Organizer: 2017年生命科学系学会合同年次大会