A study of epigentic reprogramming mechanismin head and neck cancer

• Project/Area Number: 16K11228
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Otorhinolaryngology
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Mineta Hiroyuki 浜松医科大学, 医学部, 教授 (40190714)
• Co-Investigator(Kenkyū-buntansha): 三澤 清 浜松医科大学, 医学部附属病院, 講師 (90334979) ; 遠藤 志織 浜松医科大学, 医学部附属病院, 診療助教 (10625205)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: DNA脱メチル化 / エピゲノムリプログラミング / 頭頸部がん / エピゲノム / リプログラミング / 転写因子 / 頭頸部癌 / 不均一性 / シングルセル解析

Outline of Final Research Achievements

DNA demethylation is necessary for the epigenetic reprogramming.The ten eleven translocation protein (TET) might function as a 5-methylcytosine (5mC) oxidase and potentially as a DNA demethylase.TET belongs to a family of three proteins, namely TET1, TET2, and TET3, which catalyze the successive oxidation of 5mC
to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). The 5-hmC profiles in primary tumors may be used to identify patients with positive lymph node metastasis and high tumor stage that are at a higher risk of recurrence. The methylation status of TET3 was independently associated with aggressive tumor behavior and a global effect on DNA methylation status in head and neck cancer.
We conclude that the demethylation of promoter DNA may be a necessary step in the epigenetic reprogramming of head and neck cancer.

Academic Significance and Societal Importance of the Research Achievements

頭頸部癌は予後不良の癌腫の一つである。腫瘍発生のメカニズムは不明な点た多い。今回我々は、DNA脱メチル化が、頭頸部癌発生の重要な機序の一つであると考えた。DNA脱メチル化酵素(TET)は、酸化酵素であり5mCを5hmCへと脱メチル化させる作用を持つ。5hmCは、リンパ節転移、高悪性度頭頸部癌症例で低レベルであった。TET3遺伝子高メチル化は、高悪性度頭頸部癌症例で認められた。さらに癌抑制遺伝子群の高メチル化も認め、悪性度を示す因子であることを解明した。
今回の研究で、エピゲノムリプログラミング調節機構の解明と新たな頭頸部癌の治療の開発の可能性を示すことができた。

Research Products

• [Int'l Joint Research] University of Michigan/Head and Neck Cancer Biology(米国)
• [Journal Article] Analysis of Site-Specific Methylation of Tumor-Related Genes in Head and Neck Cancer: Potential Utility as Biomarkers for Prognosis (2018)
  • Author(s): Misawa Kiyoshi、Mochizuki Daiki、Imai Atsushi、Mima Masato、Misawa Yuki、Mineta Hiroyuki
  • Journal Title: Cancers Volume: 10 Issue: 1 Pages: 27-27
  • DOI: 10.3390/cancers10010027
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant Epigenetic Regulation in Head and Neck Cancer Due to Distinct EZH2 Overexpression and DNA Hypermethylation (2018)
  • Author(s): Mochizuki Daiki、Misawa Yuki、Kawasaki Hideya、Imai Atsushi、Endo Shiori、Mima Masato、Yamada Satoshi、Nakagawa Takuya、Kanazawa Takeharu、Misawa Kiyoshi
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 12 Pages: 3707-3707
  • DOI: 10.3390/ijms19123707
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] BSND is a novel immunohistochemical marker for oncocytic salivary gland tumors (2018)
  • Author(s): "Shinmura K, Kato H, Kawanishi Y, Kamo T, Inoue Y, Yoshimura K, Sugiyama K, Misawa K, Hosokawa S, Mineta H, Sugimura H
  • Journal Title: Pathol Oncol Res Volume: 24(2) Issue: 2 Pages: 439-444
  • DOI: 10.1007/s12253-017-0248-9
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of epigenetic inactivation of vascular endothelial growth factor receptors in head and neck squamous cell carcinoma. (2017)
  • Author(s): Misawa Y, Misawa K, Kawasaki H, Imai A, Mochizuki D, Ishikawa R, Endo S, Mima M, Kanazawa T, Iwashita T, Mineta H.
  • Journal Title: Tumour Biol. Volume: 39 Issue: 7 Pages: 1-15
  • DOI: 10.1177/1010428317711657
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic silencing of SALL3 is an independent predictor of poor survival in head and neck cancer (2017)
  • Author(s): Misawa K, Mochizuki D, Imai A, Misawa Y, Endo S, Mima M, Kawasaki H, Carey TE, Kanazawa T
  • Journal Title: Clin Epigenetics Volume: 9 Issue: 1 Pages: 64-64
  • DOI: 10.1186/s13148-017-0363-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genes encoding neuropeptide receptors are epigenetic markers in patients with head and neck cancer: a site-specific analysis (2017)
  • Author(s): Misawa K, Imai A, Mochizuki D, Misawa Y, Endo S, Hosokawa S, Ishikawa R, Mima M, Shinmura K, Kanazawa T, Mineta H
  • Journal Title: Oncotarget Volume: 8(44) Issue: 44 Pages: 76318-76328
  • DOI: 10.18632/oncotarget.19356
  • Peer Reviewed / Open Access
• [Journal Article] Risk and prognostic factors for multiple primary carcinomas in patients with head and neck cancer (2017)
  • Author(s): Hosokawa S, Takahashi G, Okamura J, Imai A, Mochizuki D, Takizawa Y Yamatodani T, Misawa K, Mineta H
  • Journal Title: Jpn J Clin Oncol Volume: 48(2) Issue: 2 Pages: 124-129
  • DOI: 10.1093/jjco/hyx178
  • Peer Reviewed / Open Access
• [Journal Article] "Site-specific methylation patterns of the GAL and GALR1/2 genes in head and neck cancer: potential utility as biomarkers for prognosis (2017)
  • Author(s): Misawa K, Mochizuki D, Endo S, Mima M, Misawa Y, Imai A, Shinmura K, Kanazawa T, Carey TE, Mineta H
  • Journal Title: Mol carcinogenesis Volume: 56(3) Issue: 3 Pages: 1107-1116
  • DOI: 10.1002/mc.22577
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Prognostic value of aberrant promoter hypermethylation of tumor-related genes in early-stage head and neck cancer (2016)
  • Author(s): Misawa K, Mochizuki D, Imai A, Endo S, Mima M, Misawa Y, Kanazawa T, Carey TE, Mineta H
  • Journal Title: Oncotarget Volume: 24 Issue: 18 Pages: 26087-26098
  • DOI: 10.18632/oncotarget.8317
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Late recurrence of breast carcinoma metastasis to the hypopharynx: a case report (2016)
  • Author(s): Izumi C, Misawa K, Endo S, Sugiyama K, Mochizuki D, Imai A, Mima M, Yamatodani T, Mineta H
  • Journal Title: SpringerPlus Volume: 5 Issue: 1 Pages: 599-599
  • DOI: 10.1186/s40064-016-2226-1
  • Peer Reviewed / Open Access
• [Journal Article] Human papillomavirus-associated small cell carcinoma/neuroendocrine carcinoma of the oropharynx: A report of two cases (2016)
  • Author(s): Misawa K, Kawasaki H, Matsuo R, Sugiyama K, Mochizuki D, Endo S, Imai A, Misawa Y, Yamatodani T, Mizuta K, Mineta H
  • Journal Title: SpringerPlus Volume: 5(1) Issue: 1 Pages: 1847-1847
  • DOI: 10.1186/s40064-016-3501-x
  • Peer Reviewed / Open Access
• [Journal Article] Abnormal Expressions of DNA Glycosylase Genes NEIL1, NEIL2, and NEIL3 Are Associated with Somatic Mutation Loads in Human Cancer. (2016)
  • Author(s): Shinmura K, Kato H, Kawanishi Y, Igarashi H, Goto M, Tao H, Inoue Y, Nakamura S, Misawa K, Mineta H, Sugimura H.
  • Journal Title: Oxidative Medicine and Cellular Longevity Volume: 2016 Issue: 1 Pages: 1546392-1546392
  • DOI: 10.1155/2016/1546392
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] The epigenetic feedback loop of the CpG demethylase TET family genes in head and neck cancers (2018)
  • Author(s): 三澤 清、金澤丈治、峯田周幸
  • Organizer: 第77回日本癌学会
• [Presentation] 頭頸部癌における18番長腕23遺伝子のプロモーター領域のメチル化について (2017)
  • Author(s): 三澤 清、望月大極、今井篤志、岡村純、遠藤志織、三澤由幾、金澤丈治、武林悟、峯田周幸
  • Organizer: 第118回日本耳鼻咽喉科学会総会
• [Presentation] 部位別のエピジェネティック解析について (2017)
  • Author(s): 三澤 清、望月大極、今井篤志、岡村純、三澤由幾、金澤丈治、細川誠二、峯田周幸
  • Organizer: 第41回日本頭頸部癌学会
• [Presentation] Genes encoding neuropeptide receptors are epigenetic markers in patients with head and neck cancer: a site-specific analysis. (2017)
  • Author(s): Kiyoshi Misawa, Takeharu Kanazawa, Yuki Misawa, Hiroyuki Mineta
  • Organizer: AOGIN 2017 TOKYO Meeting
  • Int'l Joint Research
• [Presentation] Prognostic value of aberrant promoter hypermethylation of tumor-related genes in early-stage head and neck cancer (2016)
  • Author(s): 三澤 清、金澤丈治、峯田周幸
  • Organizer: 第75回日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Prognostic value of aberrant promoter hypermethylation of tumor-related genes in early-stage head and neck cancer (2016)
  • Author(s): Kiyoshi Misawa, Takeharu Kanazawa, Yuki Misawa, Hiroyuki Mineta
  • Organizer: AHNS 9th International Conference 2016
  • Place of Presentation: シアトル
  • Year and Date: 2016-07-15
  • Int'l Joint Research