Eradication of cancer cells by controlling Max and/or nucleostemin expression

• Project/Area Number: 25293082
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Saitama Medical University
• Principal Investigator: Okuda Akihiko 埼玉医科大学, 医学部, 教授 (60201993)
• Co-Investigator(Kenkyū-buntansha): KATO HIDEMASA 埼玉医科大学, 医学部, 講師 (50292123) ; HIRASAKI MASATAKA 埼玉医科大学, 医学部, 助教 (10522154) ; EMA MASATSUGU 滋賀医科大学, 動物生命科学研究センター, 教授 (60359578)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2015: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2013: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: ES細胞 / がん細胞 / 細胞増殖 / アポトーシス / c-Myc / Nucleostemin / Max / 癌細胞

Outline of Final Research Achievements

In this study, we explored the molecular bases defining the similarities between ES cells and cancer cells through the analyses of Myc and nucleostemin which are both known as important regulators in both cell types. First, we demonstrated that apoptotic phenotype of nucleostemin-null ES cells was erased by the forced expression of Nanog or Esrrb. As to the Myc studies, we demonstrated that apoptotic phenotype overexpressed with Myc in normal somatic cells reflect the intrinsic activity of Myc free from Max association which becomes evident because the amount of Myc protein exceeds much more than that of the endogenous Max due the forced expression. Furthermore, our data demonstrated that ES cells and cancer cells, but not normal somatic cells, bear proteins which suppress the intrinsic apoptotic inducing activity of Myc which is liberated from the regulation by Max.

Research Products

• [Int'l Joint Research] ソーク研究所(米国)
• [Journal Article] Max as a biological blockade that restricts meiotic process in ESCs. (2016)
  • Author(s): Suzuki A, Hirasaki M, Hishida T, Okamura D, Wu J, Ueda A, Nishimoto M, Nakachi Y, Mizuno Y, Okazaki Y, Matsui Y, *Izpisua Belmonte JC, Okuda A.
  • Journal Title: Nat Commun Volume: 7 Issue: 1 Pages: 11056-11056
  • DOI: 10.1038/ncomms11056
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combined overexpression of JARID2, PRDM14, ESRRB, and SALL4A dramatically improves efficiency and kinetics of reprogramming to induced pluripotent stem cells. (2016)
  • Author(s): Iseki H, Nakachi Y, Hishida T, Yamashita-Sugahara Y, Hirasaki M, Ueda A, Tanimoto Y, Iijima S, Sugiyama F, Yagami K, Takahashi S, Okuda A, Okazaki Y
  • Journal Title: Stem Cells Volume: 34 Issue: 2 Pages: 322-333
  • DOI: 10.1002/stem.2243
  • Peer Reviewed
• [Journal Article] A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain deficiency. (2016)
  • Author(s): Kohda M, Mizuno Y, Hirata T, Yatsuka Y, Yamashita, Okuda A, Borna NN, Banshoya K, Ohnuma K, Suzuki T, Nagao A, Maehata H, Matsuda F, Higasa K, Nagasaki M, Yasuda J, Yamamoto M, Fushimi T, Shimura M, Kaiho-Ichimoto K, Harashima H, Yamazaki T, Mori M, Murayama K, Ohtake A, Okazaki Y.
  • Journal Title: PLoS Genetics: Volume: 12(1) Issue: 1 Pages: e1005679-e1005679
  • DOI: 10.1371/journal.pgen.1005679
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Dzip3 regulates developmental genes in mouse embryonic stem cells by reorganizing 3D chromatin conformation. (2015)
  • Author(s): Inoue D, Aihara H, Sato T, Mizusaki H, Doiguchi M, Higashi M, Imamura Y, Yoneda M, Miyanishi T, Fujii S, Okuda A, Nakagawa T, Ito T
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 16567-16567
  • DOI: 10.1038/srep16567
  • NAID: 120006986837
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Forced expression of Nanog or Esrrb preserves the ESC status in the absence of nucleostemin expression (2015)
  • Author(s): Katano M, Ema M, Nakachi Y, Mizuno Y, Hirasaki M, Suzuki A, Ueda A, Nishimoto M, Takahashi S, Okazaki, Okuda A.
  • Journal Title: STEM CELLS Volume: 33 Issue: 4 Pages: 1089-1101
  • DOI: 10.1002/stem.1918
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Functional crosstalk between Myc and PI3K signaling for supporting unlimited self-renewal of embryonic stem cells (2015)
  • Author(s): Hishida T, Nakachi Y, Mizuno Y, Katano M, Okazaki Y, Ema M, Takahashi S, Hirasaki M, Suzuki A, Ueda A, Nishimoto M, Hishida-Nozaki Y, Vazquez-Ferrer E, Sancho-Martinez I, Izpisua Belmonte JC, Okuda A.
  • Journal Title: STEM CELLS Volume: 33 Issue: 3 Pages: 713-725
  • DOI: 10.1002/stem.1893
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Ccr4-Not complex components as regulators of transition from partial to genuine induced pluripotent stem cells (2014)
  • Author(s): Kamon M, Katano M, Hiraki K, Hishida T, Nakachi Y, Mizuno Y, Okazaki Y, Suzuki A, Hirasaki M, Ueda A, Nishimoto M, Kato H, Okuda A.
  • Journal Title: Stem Cells and Development Volume: 23 Issue: 18 Pages: 2170-2179
  • DOI: 10.1089/scd.2013.0326
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Genomic Aspects of Common Diseases (2014)
  • Author(s): Muramatsu M, Okuda A, and Okazaki Y
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 452 Issue: 2 Pages: 211-212
  • DOI: 10.1016/j.bbrc.2014.09.036
• [Journal Article] Establishment of a novel model for chondrogenesis using murine embryonic stem cells carrying mutant ALK2 associated with fibrodysplasia ossificans progressive (2014)
  • Author(s): Fujimoto M, Ohte S, Shin M, Yoneyama K, Osawa K, Miyamoto A, Tsukamoto S, Mizuta T, Kokabu S, Machiya A, Okuda A, Suda N, and Katagiri T.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 455 Pages: 347-352
  • Peer Reviewed
• [Journal Article] Striking similarity in the gene expression levels of individual Myc module members among ESCs, EpiSCs, and partial iPSCs (2013)
  • Author(s): Masataka Hirasaki, Keiko Hiraki-Kamon, Masayoshi Kamon, Ayumu Suzuki, Miyuki Katano, Masazumi Nishimoto, Akihiko Okuda
  • Journal Title: PLoS One Volume: 8 Issue: 12 Pages: e83769-e83769
  • DOI: 10.1371/journal.pone.0083769
  • Peer Reviewed
• [Journal Article] In vivo function and evolution of the eutherian-specific pluripotency marker UTF1. (2013)
  • Author(s): Nishimoto M, Katano M, Yamagishi T, Hishida T, Kamon M, Nabeshima Y, Nabeshima Y, Katsura Y, Satta Y, Deakin J E, Graves J A M, Kuroki Y, Ono R, Ishino F, Okazaki Y, Kato H and Okuda A.
  • Journal Title: PLoS One Volume: 8 Issue: 7 Pages: 68119-68119
  • DOI: 10.1371/journal.pone.0068119
  • Peer Reviewed
• [Journal Article] Abundant nucleostemin expression supports the undifferentiated properties of germ cell tumors (2013)
  • Author(s): Uema, N., Ooshio, T., Harada, K., Naito, M., Naka, K., Hoshii, T., Tadokoro, Y., Ohta, K., Ali, M.A., Katano, M., Soga, T., Nakanuma, Y., Okuda, A., Hirao, A.
  • Journal Title: Am. J. Pathol. Volume: 183 Issue: 2 Pages: 592-603
  • DOI: 10.1016/j.ajpath.2013.04.018
  • Peer Reviewed
• [Journal Article] Transcription factors interfering with dedifferentiation induce cell type-specific transcriptional profiles. (2013)
  • Author(s): Hikichi T, Matoba R, Ikeda T, Watanabe A, Yamamoto T, Yoshitake S, Tamura-Nakano M, Kimura T, Kamon M, Shimura M, Kawakami K, Okuda A, Okochi H, Inoue T, Suzuki A, Masui S.
  • Journal Title: Proceeding of the National Academy of Sciences of USA Volume: 110 Issue: 16 Pages: 6412-6417
  • DOI: 10.1073/pnas.1220200110
  • NAID: 120005244176
  • Peer Reviewed
• [Journal Article] Max is a repressor of germ-cell-related gene expression in mouse embryonic stem cells (2013)
  • Author(s): Maeda, I., Okamura, D., Tokitake, Y., Ikeda, M, Kawaguchi, H., Mise, N., Abe, K., Noce, T., Okuda, A, Matsui, Y
  • Journal Title: Nature Communications Volume: 4 Issue: 1 Pages: 1754-1754
  • DOI: 10.1038/ncomms2780
  • Peer Reviewed
• [Presentation] Max known as a Myc indispensable partner protein functions as a molecular blockade of meiotic entry (2015)
  • Author(s): Akihiko Okuda, Ayumu Suzuki, Masataka Hirasaki, Atsushi Ueda
  • Organizer: 第38回日本分子生物学会 第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸 ポートアイランド (兵庫県神戸市)
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] マウスES細胞における減数分裂抑制機構の発見 (2015)
  • Author(s): 鈴木 歩、平崎正孝、上田 篤、松居靖久、奥田晶彦
  • Organizer: 第38回日本分子生物学会 第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸 ポートアイランド (兵庫県神戸市)
  • Year and Date: 2015-12-01
• [Presentation] Casein kinaseとJmjd3の真獣類発生過程における細胞での概日リズム形成における役割 (2015)
  • Author(s): 西本正純、奥田晶彦、大西芳秋
  • Organizer: 第38回日本分子生物学会 第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸 ポートアイランド (兵庫県神戸市)
  • Year and Date: 2015-12-01
• [Presentation] マウスES細胞においてNucleosteminノックアウトによる未分化性の消失はNanogもしくはEsrrbタンパク質強制発現により回避される (2014)
  • Author(s): 片野 幸、水野洋介、仲地 豊、平崎正孝、鈴木 歩、西本正純、岡崎康司
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: 神奈川県横浜市 (パシフィコ横浜）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] 真獣類の発生過程におけるPer2とCKIの発現は概日リズム形成に重要である (2014)
  • Author(s): 西本正純、奥田晶彦、大西芳秋
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: 神奈川県横浜市 (パシフィコ横浜）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] ミトコンドリア呼吸鎖異常症の原因遺伝子の包括的大規模解析 (2014)
  • Author(s): 木下善仁、徳澤佳美、神田将和、森山陽介、水野洋介、菅原（山下）泉、田丸俊輔、栃木秀乃、上原奈津美、仲地豊、八塚由紀子、入月浩美、鈴木聡美、Nurun Nahar Borna、平田智子、的場奈々、加藤英政、奥田晶彦、森雅人、安嶋まさみ、原嶋宏子、山崎太郎、村山圭、大竹明、岡崎康司
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: 神奈川県横浜市 (パシフィコ横浜）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Jarid2 improves the kinetics and efficiency of transcription-based reprogramming (2013)
  • Author(s): Hiroyoshi Iseki,Yutaka Nakachi, Tomoaki Hishida, Yoko Tanimoto,Fumihiko Sugiyama, Ken-ichi Yagami, Akihiko Okuda, Yasushi Okazaki
  • Organizer: 11th annual meeting of ISSCR
  • Place of Presentation: Boston, USA
• [Presentation] Underlying the molecular bases of cell death phenotype of Max-null embryonic stem cells (2013)
  • Author(s): Akihiko Okuda
  • Organizer: Small RNAs to Stem Cells & Epigenetic Reprogramming Asia-2013 Meeting
  • Place of Presentation: 東京都文京区
• [Presentation] Mycモジュール遺伝子メンバーのほとんどが、ES細胞とEpiblast幹細胞の両者で同レベルの発現を示す (2013)
  • Author(s): 平崎正孝、片野 幸、鈴木 歩、西本正純、奥田晶彦
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸市
• [Presentation] MaxノックアウトES細胞の激しい細胞死はヌクレオチド欠乏に伴う複製ストレスにより引き起こされる (2013)
  • Author(s): 鈴木 歩、菱田友昭、平崎正孝、曽我朋義、奥田晶彦
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸市
• [Presentation] ヒト分化多能性細胞の分化の改善 (2013)
  • Author(s): 加藤英政、平木啓子、栄徳勝光、清澤秀孔、奥田晶彦
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸市
• [Remarks] 精子・卵子形成の為の減数分裂を開始させる仕組みを発見
  • URL: http://www.saitama-med.ac.jp/genome/press_release_03_30_16.pdf#search='%E5%9F%BC%E7%8E%89%E5%8C%BB%E7%A7%91%E5%A4%A7%E5%AD%A6+%E7%B2%BE%E5%AD%90+%E5%A5%A5%E7%94%B0%E6%99%B6%E5%BD%A6'
• [Remarks] 共同通信PRワイヤーからのプレスリリース
  • URL: http://www.kyodo.co.jp/pr/2016-03-30_1539373/
• [Remarks] 埼玉医科大学 ゲノム医学研究センター