Tumor progression through epigenetics remodeling by RB-PGAM

• Project/Area Number: 17K14992
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Kanazawa University
• Principal Investigator: Kohno Susumu 金沢大学, がん進展制御研究所, 特任助教 (30625463)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: RB / PGAM / KDM5A / エピジェネティクス

Outline of Final Research Achievements

The metabolic intermediates produced in the glycolytic or TCA cycle are utilized in various pathways. We focused on the tumor suppressor gene RB, which is frequently inactivated in the malignant progression of cancer, and found that the expression of glycolytic enzyme PGAM1 is regulated by RB. In this study, we focused on the metabolic changes caused by RB inactivation and analyzed the impact given by the metabolic alteration on epigenetics. As a result, RB regulates global methylation in gastric cancer via KDM5A, and it is revealed that various glycolytic enzymes are controlled by the RB-KDM5A axis. In addition, we found that PGAM contributes RB dependent cell differentiation in myogenesis of C2C12 and adipogenesis of 3T3L1.

Academic Significance and Societal Importance of the Research Achievements

これまでに、何故がん細胞は、グルコースを積極的に利用するのか、その生理的意義と本質に迫ることができていない。本研究では、がん悪性進展課程におけるRBの不活性化に伴い、グルコースの利用が下がるという、従来の「がん特異的代謝」の概念とは逆の現象に着目し、エピジェネティクスの観点からがん代謝の理解を試みたものである。

Research Products

• [Journal Article] Regucalcin confers resistance to amyloid-β toxicity in neuronally differentiated PC12 cells (2018)
  • Author(s): Murata Tomiyasu、Yamaguchi Masayoshi、Kohno Susumu、Takahashi Chiaki、Kakimoto Mitsumi、Sugimura Yukiko、Kamihara Mako、Hikita Kiyomi、Kaneda Norio
  • Journal Title: FEBS Open Bio Volume: 8 Issue: 3 Pages: 349-360
  • DOI: 10.1002/2211-5463.12374
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2 (2018)
  • Author(s): Nishimura Tatsunori、Nakata Asuka、Chen Xiaoxi、Nishi Kurumi、Meguro-Horike Makiko、Sasaki Soichiro、Kita Kenji、Horike Shin-ichi、Saitoh Kaori、Kato Keiko、Igarashi Kaori、Murayama Takahiko、Kohno Susumu、Takahashi Chiaki、Mukaida Naofumi、Yano Seiji、Soga Tomoyoshi、Tojo Arinobu、Gotoh Noriko
  • Journal Title: Oncogene Volume: 38 Issue: 14 Pages: 2464-2481
  • DOI: 10.1038/s41388-018-0589-1
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-140 mediates RB tumor suppressor function to control stem cell-like activity through interleukin-6. (2017)
  • Author(s): Yoshida A, Kitajima S, Li F, Chaoyang C, Yujiro T, Susumu K, Wan Y, Naoyuki H, Hayato M, Nishimoto Y, Nagatani N, Nishiuchi T, Thai T C, Suzuki S, Nakao S, Tanaka T, Hirose O, Barbie D A and Takahashi C.
  • Journal Title: Oncotarget Volume: 印刷中 Issue: 8 Pages: 13872-85
  • DOI: 10.18632/oncotarget.14681
  • NAID: 120006226780
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Glucoraphanin ameliorates obesity and insulin resistance through adipose tissue browning and reduction of metabolic endotoxemia in mice. (2017)
  • Author(s): Nagata N, Xu L, Kohno S, Ushida Y, Aoki Y, Umeda R, Fuke N, Zhuge F, Ni Y, Nagashimada M, Takahashi C, Suganuma H, Kaneko S and Ota T.
  • Journal Title: Diabetes Volume: 印刷中 Issue: 5 Pages: 1222-1236
  • DOI: 10.2337/db16-0662
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The RB?IL-6 axis controls self-renewal and endocrine therapy resistance by fine-tuning mitochondrial activity (2017)
  • Author(s): Kitajima S、Yoshida A、Kohno S、Li F、Suzuki S、Nagatani N、Nishimoto Y、Sasaki N、Muranaka H、Wan Y、Thai T C、Okahashi N、Matsuda F、Shimizu H、Nishiuchi T、Suzuki Y、Tominaga K、Gotoh N、Suzuki M、Ewen M E、Barbie D A、Hirose O、Tanaka T、Takahashi C
  • Journal Title: Oncogene Volume: 36 Issue: 36 Pages: 5145-5157
  • DOI: 10.1038/onc.2017.124
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A distinct function of the retinoblastoma protein in the control of lipid composition identified by lipidomic profiling (2017)
  • Author(s): Muranaka H、Hayashi A、Minami K、Kitajima S、Kohno S、Nishimoto Y、Nagatani N、Suzuki M、Kulathunga L A N、Sasaki N、Okada N、Matsuzaka T、Shimano H、Tada H、Takahashi C
  • Journal Title: Oncogenesis Volume: 6 Issue: 6 Pages: e350-e350
  • DOI: 10.1038/oncsis.2017.51
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] KDM5AとRBが制御する代謝分子の探索 (2018)
  • Author(s): 3.河野晋, 岡橋伸幸, 松田史生, 清水浩, 髙橋智聡.
  • Organizer: 第6回がんと代謝研究会
• [Presentation] RB controls differentiation through positive regulation of phosphoglycerate mutases. (2018)
  • Author(s): Kohno S and Takahashi C.
  • Organizer: Abcam Cancer and Metabolism conference
  • Int'l Joint Research
• [Presentation] ヒストン脱メチル化酵素KDM5AとRBが制御する代謝分子の探索. (2018)
  • Author(s): 河野晋, 岡橋伸幸, 松田史生, 清水浩, 髙橋智聡.
  • Organizer: 第1回 金沢大学がん進展制御研究所・国立がん研究センター研究所若手研究発表会
• [Presentation] ストン脱メチル化酵素KDM5AとRBが制御する代謝分子の探索. (2018)
  • Author(s): 河野晋, 岡橋伸幸, 松田史生, 清水浩, 髙橋智聡.
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 前立腺がんにおけるRBホモ欠損に伴う脆弱性の獲得 (2017)
  • Author(s): 河野晋, Paing Linn, 髙橋智聡
  • Organizer: 第5回がんと代謝研究会
• [Presentation] 悪性進展過程におけるRBの代謝調節機能 (2017)
  • Author(s): 河野晋, 岡橋伸幸, 松田史生, 清水浩, 髙橋智聡
  • Organizer: 2017年度生命科学系学会合同年次大会