Elucidation of mechanisms for tumor malignancy and radioresistance by crosstalk between Hypoxia, circadian rhythm and metabolic regulation

• Project/Area Number: 25861088
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Radiation science
• Research Institution: Kyoto University
• Principal Investigator: KOBAYASHI minoru 京都大学, 医学(系)研究科(研究院), 特定研究員 (40644894)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 低酸素 / 概日リズム / 放射線抵抗性

Outline of Final Research Achievements

Previously, crosstalk between circadian rhythm and hypoxia response were reported but this mechanism is unclear. So, we analyzed mechanisms of crosstalk between PER2 which is one of circadian regulated genes, and hypoxia response. Then we revealed that the short sequence near transcription start site is important for PER2 gene upregulation by hypoxia but Hypoxia-Inducible Factor (HIF) does not contribute to this regulation. And we found that PER2 protein N-terminal region enhance transactivation activity from HIF-1 C-terminal transactivation domain.
In future, by clarify the mechanisms of crosstalk between circadian rhythm and hypoxia responses, we expect unraveling of physiological and pathophysiological significance in this crosstalk.

Research Products

• [Journal Article] UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1alpha (2015)
  • Author(s): Goto Y, Zeng L, YeomCJ, Zhu Y, Morinibu A, Shinoyam K, Kobayashi M, Hirota K, Itasaka S, Yoshimura M, Tanimoto K, Sowa T, Menju T, Sonobe M, Kakeya H, Toi M, Date H, Hammond EM, Hiraoka M, Harada H.
  • Journal Title: Nat Commun Volume: 6 Issue: 1 Pages: 1-10
  • DOI: 10.1038/ncomms7153
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant IDH3α expression promotes malignant tumor growth by inducing HIF-1-mediated metabolic reprogramming and angiogenesis. (2014)
  • Author(s): Zeng L, Morinibu A, Kobayashi M, Zhu Y, Wang X, Goto Y, Yeom CJ, Zhao T,Hirota K, Shinomiya K, Itasaka S, Yoshimura M, Guo G, Hammond EM, Hiraoka M, Harada H.
  • Journal Title: Oncogene Volume: epub Issue: 36 Pages: 4758-4766
  • DOI: 10.1038/onc.2014.411
  • Peer Reviewed / Open Access
• [Journal Article] HIF-1-mediated metabolic reprogramming reduces ROS levels and facilitates the metastatic colonization of cancers in lungs. (2014)
  • Author(s): 1. Zhao T, Zhu Y, Morinibu A, Kobayashi M, Shinomiya K, Itasaka S, Yoshimura M, Guo G, Hiraoka M, Harada H.
  • Journal Title: Scientific Reports Volume: 4.3793 Issue: 1 Pages: 1-7
  • DOI: 10.1038/srep03793
  • Peer Reviewed / Open Access
• [Journal Article] 低酸素ストレスとHIF (2013)
  • Author(s): 小林 稔、原田 浩
  • Journal Title: 生化学 Volume: 85 Pages: 187-195
  • NAID: 10031164201
• [Presentation] 時計遺伝子PER2と低酸素応答機構の相互作用メカニズムの解析 (2014)
  • Author(s): 小林 稔、平岡 真寛、原田 浩
  • Organizer: 第12回がんとhypoxia研究会
  • Place of Presentation: 佐賀
  • Year and Date: 2014-11-21 – 2014-11-22
• [Presentation] Cancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels. (2014)
  • Author(s): Minoru Kobayashi, Hiraoka Masahiro, Harada Hiroshi
  • Organizer: Radiation Research Society 60th Annual Meeting
  • Place of Presentation: Las Vegas, Nevada
  • Year and Date: 2014-09-21
• [Presentation] IDH3はHIF-1αを安定化して腫瘍増殖を亢進する
  • Author(s): 小林 稔. 曽 麗華. 後藤 容子. 井上 実. 板坂 聡. 吉村 通央. 原田 浩. 平岡 真寛
  • Organizer: 第19回 国際癌治療増感研究会
  • Place of Presentation: 東京
• [Remarks] 京都大学大学院 医学研究科 放射線腫瘍学・画像応用治療学ホームページ
  • URL: http://radiotherapy.kuhp.kyoto-u.ac.jp/biology/
• [Remarks] Nature Communications誌に掲載された研究成果のプレスリリース（京大ホームページ）
  • URL: http://www.kyoto-u.ac.jp/ja/research/research_results/2014/150113_1.html
• [Remarks] Nature Communications誌に掲載された論文が、「注目の論文」にて紹介されたページ
  • URL: http://www.natureasia.com/ja-jp/ncomms/abstracts/61434