Mechanism of suppression of Notch signaling by CDX1 and CDX2 in colon cancer cells

• Project/Area Number: 16K18415
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: University of Fukui
• Principal Investigator: Hori Kazuya 福井大学, 学術研究院医学系部門, 助教 (50749059)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 大腸癌 / CDX1 / CDX2 / Notchシグナル / シグナル伝達 / 腫瘍学

Outline of Final Research Achievements

In this study, we found that CDX1 and CDX2, which are homeobox transcription factors expressed in intestinal epithelial cells, directly regulate Notch signaling via RBP-J, an effector of Notch signaling. In addition, through mass spectrometry analysis of CDX2, we identified a NAD-dependent deacetylase Sirtuin1, which has been reported to regulate the Notch signaling in several cancers. We showed that, in HCT116 cells, CDX2 strongly suppresses the Notch activity, while Sirtuin1 inhibits the suppression of Notch by CDX2. These results suggest that CDX1 and CDX2 at least partially compete Sirtuin1 to regulate the activity of Notch signaling in colon cancer cells.

Research Products

• [Journal Article] RBPJ/CBF1 interacts with L3MBTL3/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A/LSD1 (2017)
  • Author(s): Xu T, Park SS, Giaimo BD, Hall D, Ferrante F, Ho DM, Hori K, Anhezini L, Ertl I, Bartkuhn M, Zhang H, Milon E, Ha K, Conlon KP, Kuick R, Govindarajoo B, Zhang Y, Sun Y, Dou Y, Basrur V, Elenitoba‐Johnson KS, Nesvizhskii AI, Ceron J, Lee CY, Borggrefe T, Kovall RA, Rual JF
  • Journal Title: The EMBO Journal Volume: 36 Issue: 21 Pages: 3232-3249
  • DOI: 10.15252/embj.201796525
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Suppression of intestinal cancer stemness and malignant progression by homeoproteins CDX1 and CDX2 (2017)
  • Author(s): Aoki K, Hori K
  • Organizer: 日本薬学会北陸支部第129回例会
• [Presentation] Suppression of intestinal cancer stemness and malignant progression by intestine-specific homeoproteins CDX1 and CDX2 (2016)
  • Author(s): Kazuya Hori, Mako Nakaya, Takanori Goi, Akio Yamaguchi, Shunichiro Iemura, Tohru Natsume, Makoto M. Taketo, Manabu Sugai, Koji Aoki
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-30
• [Presentation] Enhanced intestinal mucosal barrier function by homeoprotein CDX2 through autophagy (2016)
  • Author(s): Koji Aoki, Mako Nakaya, Kazuya Hori, Katsuya Okawa, Isei Tanida, Taira Kobayashi, Hitomi Mimuro, Takahito Sanada, Chihiro Sasakawa, Makoto M. Taketo, Manabu Sugai
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-30
• [Presentation] Blocking intestinal cancer stemness and malignant progression by intestine-specific homeoproteins CDX1 and CDX2 (2016)
  • Author(s): Koji Aoki, Kazuya Hori
  • Organizer: 第３回北陸エピジェネティクス研究会
  • Place of Presentation: AOSSA（福井県福井市）
  • Year and Date: 2016-11-21