Regulation of metabolism by RB tumor suppressor gene

• Project/Area Number: 26290037
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Kanazawa University
• Principal Investigator: Takahashi Chiaki 金沢大学, がん進展制御研究所, 教授 (50283619)
• Co-Investigator(Renkei-kenkyūsha): Hayashi Naoyuki 金沢大学, がん進展制御研究所, 助教 (50253456) ; Kitajima Syunsuke 金沢大学, がん進展制御研究所, 特任助教 (90566465) ; Shamma Awad 金沢大学, がん進展制御研究所, 助教 (50402839) ; Kohno Susumu 金沢大学, がん進展制御研究所, 研究員 (30625463) ; Sasaki Nobunari 金沢大学, がん進展制御研究所, 研究員 (40415170)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2014: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: がん代謝 / RB / 解糖系 / 脂質代謝 / PGAM / がん抑制遺伝子 / がん / 代謝 / がん幹細胞 / コレステロール / 糖代謝 / グルタミン

Outline of Final Research Achievements

We found that PGAM1 and 2 mediate function of RB tumor suppressor to regulate glycolysis. We also clarified how RB controls transcription of these genes. A further study demonstrated that PGAMs mediate RB function to control differentiation. On the other hand, we investigated the clinical significance of the RB function to control cholesterol synthesis. RB loss via increasing cholesterol synthesis recruits androgen receptor (AR) to nucleus and reduces ROS. These phenomenons were antagonized addition of statins, Lastly, we performed lipidomics analysis of RB-inactivated cells, which indicated that RB status gives significant impact on the quantitative and qualitative status of fatty acids,

Research Products

• [Int'l Joint Research] Dana-Farmer Cancer Institute/Broad Institute(米国)
• [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, Susumu K, Li F, Suzuki S, Nagatani N, Nishimoto Y, Sasaki N, Hayato M, 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 and Takahashi C
  • Journal Title: Oncogene Volume: 印刷中
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [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] Therapeutic strategy for targeting aggressive malignant gliomas by disrupting their energy balance. (2016)
  • Author(s): Hegazy AM, Yamada D, Kobayashi M, Kohno S, Ueno M, Ali MA, Ohta K, Tadokoro Y, Ino Y, Todo T, Soga T, Takahashi C and Hirao A.
  • Journal Title: J Biol Chem Volume: 291 Pages: 170-184
  • Peer Reviewed
• [Journal Article] RB tumor suppressor functions shared by stem cell and cancer cell strategies. (2016)
  • Author(s): Kohno S, Kitajima S, Sasaki N and Takahashi C.
  • Journal Title: World J Stem Cells Volume: 8 Issue: 4 Pages: 170-184
  • DOI: 10.4252/wjsc.v8.i4.170
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Primary Culture of Mouse Thyroid Calcitonin-producing Cell (C cell) Tumors. (2015)
  • Author(s): Kitajima S, Li F, Takahashi C.
  • Journal Title: Bio-Protocol Volume: 5-24
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] An in vitro system to characterize prostate cancer progression identified signaling required for self-renewal. (2015)
  • Author(s): Salah M, Nishimoto Y, Kohno S, Kondoh A, Kitajima S, Muranaka H, Nishiuchi T, Ibrahim A, Yoshida A, Takahashi C.
  • Journal Title: Mol Carcinog. Volume: in press Issue: 12 Pages: 1974-1989
  • DOI: 10.1002/mc.22444
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Undifferentiated State Induced by Rb-P53 Double Inactivation in Mouse Thyroid Neuroendocrine Cells and Embryonic Fibroblasts (2015)
  • Author(s): Kitajima S, Kohno S, Kondoh A, Sasaki N, Nishimoto Y, Li F, Mohammed MS, Muranaka H, Nagatani N, Suzuki M, Kido Y, Takahashi C
  • Journal Title: STEM CELLS Volume: - Issue: 5 Pages: 1657-1669
  • DOI: 10.1002/stem.1971
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Metabolic characterization of cultured mammalian cells by mass balance analysis, tracer labeling experiments and computer-aided simulations. (2015)
  • Author(s): Okahashi N, Kohno S, Kitajima S, Matsuda F, Takahashi C, Shimizu H.
  • Journal Title: J Biosci Bioeng. Volume: 120 Issue: 6 Pages: 725-731
  • DOI: 10.1016/j.jbiosc.2015.04.003
  • Peer Reviewed
• [Journal Article] Pleiotropic functions of RB protein in tumor suppression. (2015)
  • Author(s): Hayashi N. and Takahashi C.
  • Journal Title: Archives in Cancer Res Volume: epub
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] RECK-mediated β1-integrin regulation by TGF-β1 is critical for wound contraction in mice. (2015)
  • Author(s): Gutierrez J, Droppelmann CA, Contreras O, Takahashi C and Brandan E.
  • Journal Title: PLoS One Volume: Aug 6 Issue: 8 Pages: e0135005-e0135005
  • DOI: 10.1371/journal.pone.0135005
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Retinoblastoma Protein and MyoD Function Together to Effect the Repression of Fra-1 and In Turn Cyclin D1 During Terminal Cell Cycle Arrest Associated with Myogenesis. (2014)
  • Author(s): Rajabi H M, Takahashi C and Ewen M E.
  • Journal Title: J Biol Chem Volume: 289 Issue: 34 Pages: 23417-23427
  • DOI: 10.1074/jbc.m113.532572
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association of a murine leukaemia stem cell gene signature based on nucleostemin promoter activity with prognosis of acute myeloid leukaemia in patients. (2014)
  • Author(s): Ali MA, Naka K, Yoshida A, Fuse K, Kasada A, Hoshii T, Tadokoro Y, Ueno M, Ohta K, Kobayashi M, Takahashi C, Hirao A.
  • Journal Title: Biochem Biophys Res Commun. Volume: 450 Issue: 1 Pages: 837-843
  • DOI: 10.1016/j.bbrc.2014.06.066
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Regulation of metabolism by RB tumor suppressor gene (2017)
  • Author(s): Takahashi C.
  • Organizer: AACR Annual Meeting 2017
  • Place of Presentation: Washington/USA
  • Int'l Joint Research / Invited
• [Presentation] RB function in controlling glycolysis. (2016)
  • Author(s): Kohno S, Kitajima S and Takahashi C.
  • Organizer: Keystone Symposia
  • Place of Presentation: Banff, Canada/Fairmont Banff Springs
  • Year and Date: 2016-02-24
  • Int'l Joint Research
• [Presentation] Cooperative roles of Rb and SREBP-1 in controlling fatty acid metabolism and carcinogenesis. (2016)
  • Author(s): Muranaka H, Tada H, Hayashi A, Minami K, Kitajima S, Tange S, Suzuki T, Matsuzaka T, Shimano H and Takahashi C
  • Organizer: Keystone Symposia
  • Place of Presentation: Banff, Canada/Fairmont Banff Springs
  • Year and Date: 2016-02-23
  • Int'l Joint Research
• [Presentation] Metabolic regulation by RB tumor suppressor gene. (2016)
  • Author(s): Takahashi C.
  • Organizer: 2016 International Symposium of Cancer Center of Excellence-Innovative Research in Cancer Prevention and Treatment
  • Place of Presentation: CHANG YUNG-FA FOUNDATION International Convention Center/台北
  • Int'l Joint Research / Invited
• [Presentation] Metabolic regulation by RB tumor suppressor gene. (2016)
  • Author(s): Takahashi C.
  • Organizer: 日仏交流セミナー「癌・疾病における細胞・個体老化」
  • Place of Presentation: 京都/コープイン京都
  • Int'l Joint Research / Invited
• [Presentation] RBがん抑制遺伝子による代謝制御 (2016)
  • Author(s): 髙橋智聡
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜/パシフィコ横浜
  • Invited
• [Presentation] CONTROL OF GLUCOSE METABOLISM BY RB. (2016)
  • Author(s): Kohno S, Takahashi C
  • Organizer: Translational research in cancer cell metabolism
  • Place of Presentation: Palacio Euskalduna Jauregia /ビルバオ スペイン
  • Int'l Joint Research
• [Presentation] Phosphoglyceratemutases (PGAMs) mediate RB function to control differentiation. (2016)
  • Author(s): Kohno S and Takahashi C.
  • Organizer: Fourth International Rb Meeting
  • Place of Presentation: Hilton Columbus Downtown /コロンバス オハイオ州
  • Int'l Joint Research
• [Presentation] The Metabolic Bases for Inflammatory Phenotype Associated with RB-deficiency in Mammary Cells. (2016)
  • Author(s): Nishimoto Y, Kitajima S and Takahashi C
  • Organizer: Fourth International Rb Meeting
  • Place of Presentation: Hilton Columbus Downtown /コロンバス オハイオ州
  • Int'l Joint Research
• [Presentation] RBがん抑制遺伝子による代謝制御と細胞未分化性 (2016)
  • Author(s): 髙橋智聡, 北嶋俊輔, 河野晋
  • Organizer: 第68回日本細胞生物学会大会
  • Place of Presentation: 京都/京都テルサ
• [Presentation] Metabolic rewiring in Rb deficient cells during cancer progression. (2016)
  • Author(s): Kohno S, Okahashi N, Kitajima S Suzuki S, Tanaka T, Matsuda F, Shimizu H and Takahashi C.
  • Organizer: AACR Annual Meeting 2016
  • Place of Presentation: New Orleans USA/Ernest N. Morial Convention Center
  • Int'l Joint Research
• [Presentation] RBがん抑制遺伝子による代謝制御 (2015)
  • Author(s): 髙橋智聡
  • Organizer: 第46回高松宮妃癌研究基金国際シンポジウム
  • Place of Presentation: 東京 パレスホテル東京
  • Year and Date: 2015-11-17
  • Int'l Joint Research / Invited
• [Presentation] Cooperative roles of Rb and SREBP-1 in controlling fatty acid metabolism and carcinogenesis. (2015)
  • Author(s): Muranaka H, Tada H, Hayashi A, Minami K, Kitajima S, Tange S, Suzuki T, Matsuzaka T, Shimano H, Takahashi C.
  • Organizer: Cancer and Metabolism conference
  • Place of Presentation: 英国 Cambridge/Robinson College
  • Year and Date: 2015-09-29
  • Int'l Joint Research
• [Presentation] RB1不活性化シグナチャー解析による新規分子標的探索 (2015)
  • Author(s): 髙橋智聡
  • Organizer: 第19回日本がん分子標的治療学会学術集会
  • Place of Presentation: 松山 松山全日空ホテル
  • Year and Date: 2015-06-11
  • Invited
• [Presentation] Metabolic functions of RB tumor suppressor in controlling undifferentiated state. (2015)
  • Author(s): Takahashi C
  • Organizer: 2015 the Catholic Univ. of Korea Seoul St Mary’s Hospital Comprehensive Cancer Institute International Symposium
  • Place of Presentation: 韓国 ソウル St Mary’s Hospital
  • Year and Date: 2015-05-22
  • Int'l Joint Research / Invited
• [Presentation] がん代謝とがん幹細胞-RBがん抑制遺伝子研究から (2015)
  • Author(s): 髙橋智聡
  • Organizer: 第28回原研研究集会
  • Place of Presentation: 長崎県・長崎市・長崎大学
  • Year and Date: 2015-03-25
  • Invited
• [Presentation] The metabolic function of RB in controlling mevalonate (MVA) pathway regulates tumor progression (2015)
  • Author(s): Sasaki N, Kitajima S, Muranaka H, Shamma A, Kohno S, Takahashi C
  • Organizer: Keystone Symposia
  • Place of Presentation: Vancouver・Canada・Fairmont Hotel
  • Year and Date: 2015-01-16
• [Presentation] RBによるメバロン酸経路を介したがん悪性進展制御機構. (2014)
  • Author(s): 佐々木信成, 村中勇人, 北嶋俊輔, 河野晋, Shamma A, 髙橋智聡
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 神奈川県・横浜市・パシフィコ横浜
  • Year and Date: 2014-11-27
• [Presentation] がん抑制遺伝子RBによるSREBP-1の制御とがんにおける役割の解析 (2014)
  • Author(s): 村中勇人, 北嶋俊輔, 佐々木信成, 河野晋, 吉田晶代, 丹下正一朗, 鈴木健之, 林昭夫, 多田秀昭, Shamma A, 髙橋智聡
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 神奈川県・横浜市・パシフィコ横浜
  • Year and Date: 2014-11-27
• [Presentation] In vitro乳腺発がんモデルにおけるがん抑制遺伝子Rb, p53の機能とその作用機構の解析 (2014)
  • Author(s): 西本裕希, Mohammed M, 吉田晶代, 西内巧, 北嶋俊輔, 髙橋智聡
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 神奈川県・横浜市・パシフィコ横浜
  • Year and Date: 2014-11-27
• [Presentation] RBがん抑制遺伝子の代謝制御機構 (2014)
  • Author(s): 髙橋智聡
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 神奈川県・横浜市・パシフィコ横浜
  • Year and Date: 2014-11-26
  • Invited
• [Presentation] マウスにおいてRb1はmiR-140を介して腫瘍抑制的に作用する (2014)
  • Author(s): 吉田晶代, 北嶋俊輔, 林直之, 広瀬修, 髙橋智聡.マウスにおいてRb1はmiR-140を介して腫瘍抑制的に作用する
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 神奈川県・横浜市・パシフィコ横浜
  • Year and Date: 2014-11-25
• [Presentation] がん幹細胞と代謝- RBがん抑制遺伝子研究からのアプローチ (2014)
  • Author(s): 高橋智聡
  • Organizer: 第1３回 福井臨床薬理を考える会
  • Place of Presentation: 福井県・福井市・ユアーズホテル
  • Year and Date: 2014-11-10
  • Invited
• [Presentation] がん代謝と細胞老化制御におけるRB機能 (2014)
  • Author(s): 髙橋智聡
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 神奈川県・横浜市・パシフィコ横浜
  • Year and Date: 2014-09-27
  • Invited
• [Presentation] The metabolic function of RB in controlling mevalonate (MVA) pathway and tumor progression. (2014)
  • Author(s): Sasaki N, Muranaka H, Kitajima S, Kohno S, Shamma A and Takahashi C
  • Organizer: 第37回日本癌学会学術総会
  • Place of Presentation: 神奈川県・横浜市・パシフィコ横浜
  • Year and Date: 2014-09-27
• [Presentation] Rbによるサイトカインを介したがん悪性化制御機構の解明 (2014)
  • Author(s): 北嶋俊輔, 吉田晶代, 河野晋, 鈴木佐和子, 田中知明, 後藤典子, 髙橋智聡
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 神奈川県・横浜市・パシフィコ横浜
  • Year and Date: 2014-09-25
• [Presentation] RBの中心代謝制御機能 (2014)
  • Author(s): 河野晋, 北嶋俊輔, 吉田晶代, 鈴木佐和子, 田中知明, 佐々木信成, 村中勇人, 髙橋智聡
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 神奈川県・横浜市・パシフィコ横浜
  • Year and Date: 2014-09-25
• [Presentation] RB functions in rewiring metabolic pathways in cancer cells (2014)
  • Author(s): Chiaki Takahashi
  • Organizer: 熊本大学HIGOプログラム最先端研究セミナー
  • Place of Presentation: 熊本県・熊本市・熊本大学発生研
  • Year and Date: 2014-07-23
  • Invited
• [Presentation] マウス由来腫瘍細胞のRb1 不活性化シグニチャーとヒト乳癌の臨床像との関連 (2014)
  • Author(s): 吉田晶代, 北嶋俊輔, 廣瀬修, 田中知明, 髙橋智聡
  • Organizer: 第12回日本臨床腫瘍学会学術集会
  • Place of Presentation: 福岡県・福岡市・福岡国際会議場
  • Year and Date: 2014-07-17
• [Presentation] RB不活性化によって誘導されるがん幹細胞様未分化状態におけるPgam2の役割 (2014)
  • Author(s): 河野晋, 北嶋俊輔, 佐々木信成, 村中勇人, 鈴木佐和子, 田中知明, 岡橋伸幸, 松田史生, 清水浩, 髙橋智聡
  • Organizer: 第2回がんと代謝研究会
  • Place of Presentation: 東京都・葛飾区・東京理科大学
  • Year and Date: 2014-07-16
• [Presentation] Reductive glutamine metabolism in p53-null soft tissue sarcoma cells. (2014)
  • Author(s): Okahashi N, Matsuda F, Kohno S, Takahashi C and Shimizu H.
  • Organizer: Metabolomics 2014.
  • Place of Presentation: 山形県・鶴岡市・慶応大学鶴岡キャンパス
  • Year and Date: 2014-06-05
• [Book] 『代謝変化とエピジェテックス制御』「RBがん抑制遺伝子産物による細胞未分化性制御」 (2016)
  • Author(s): 河野晋、北嶋俊輔、佐々木信成、髙橋智聡.
  • Total Pages: 7
  • Publisher: 生化学
• [Book] 生体の科学 がん細胞の中の多様性・多層性 (2016)
  • Author(s): 西本裕希、高橋智聡
  • Publisher: 医学書院
• [Book] マウス甲状腺C細胞および線維芽細胞は高度な未分化性を獲得する. BioMedサーカス.com 最新研究情報「執筆者自身による研究論文レビュー 第35回」 (2015)
  • Author(s): 北嶋俊輔, 河野晋, 髙橋智聡
  • Publisher: BioMedサーカス.com
• [Book] 家族性腫瘍学 ― 家族性腫瘍の最新研究動向 ― II. 各論 原因遺伝子 RB1. 日本臨牀 (2015)
  • Author(s): 髙橋智聡
  • Publisher: 日本臨牀
• [Book] ニッチ細胞の遺伝子変異が発がんを誘導する？骨芽細胞の場合 (2014)
  • Author(s): 高橋 智聡
  • Total Pages: 2
  • Publisher: 羊土社
• [Remarks] 髙橋智聡研究室HP
  • URL: http://omb.w3.kanazawa-u.ac.jp/index.html
• [Remarks] 金沢大学がん進展制御研究所HP
  • URL: http://ganken.cri.kanazawa-u.ac.jp
• [Remarks] 高橋智聡研究室HP
  • URL: http://omb.w3.kanazawa-u.ac.jp
• [Remarks] Tha Takahashi Lab
  • URL: http://omb.w3.kanazawa-u.ac.jp
• [Remarks] 金沢大学がん進展制御研究所
  • URL: http://www.kanazawa-u.ac.jp/~ganken/