Suppressive role of the adaptor protein Hic-5 in anchorage-independent cell growth

• Project/Area Number: 24590390
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Showa University
• Principal Investigator: KAZUNORI Mori 昭和大学, 薬学部, 助教 (60349040)
• Co-Investigator(Kenkyū-buntansha): SHIBANUMA Motoko 昭和大学, 薬学部, 教授 (60245876) ; ISHIKAWA Fumihiro 昭和大学, 薬学部, 助教 (60515667)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 足場非依存性増殖 / がん転移抑制 / HIC-5 / 足場非依存性増殖能

Outline of Final Research Achievements

In the present study, we addressed HIC-5-dependent growth arrest mechanism under nonadherent conditions. The mechanism transcriptionally induced a CDK inhibitor (CKI), p21Cip1, in response to disruption of cell-ECM interactions. The role of HIC-5 in this mechanism was to tether KLF4, a transcription factor essential for transactivation of p21Cip1, to DNA sites in response to cellular detachment.
We also found that MMP-9 expression was upregulated by depletion of HIC-5 with RNAi, which potentially contributes to HIC-5-mediated regulation of tumor metastasis in vivo. Interestingly, ectopic expression of kinase-inactivated TGF-b type I receptor completely blocked the HIC-5 effect. Neither Smads phosphorylation nor expression of other TGF-b-targeted genes were affected by HIC-5 levels. Collectively, a new TGF-b signaling pathway has emerged contributing to cancer progression through the regulation of MMP-9 expression depending on HIC-5.

Research Products

• [Journal Article] A HIC-5- and KLF4-dependent mechanism transactivates p21(Cip1) in response to anchorage loss. (2012)
  • Author(s): Mori K, Hamanaka H, Oshima Y, Araki Y, Ishikawa F, Nose K, Shibanuma M.
  • Journal Title: The Journal of Biological Chemistry Volume: 287 Issue: 46 Pages: 38854-38865
  • DOI: 10.1074/jbc.m112.377721
  • Peer Reviewed
• [Presentation] HIC-5 regulates TGF-b-stimulated MMP-9 expression, anchorage-independent growth, and metastasis of breast cancer cells (2014)
  • Author(s): Kazunori MORI, Fumihiro ISHIKAWA, Motoko SHIBANUMA
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Adhesion-sensitive transcriptional regulation of p21Cip is dependent on the molecular scaffold HIC-5 and KLF4 (2012)
  • Author(s): Kazunori Mori, Fumihiro Ishikawa, Motoko Shibanuma
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌
• [Remarks] 昭和大学薬学部腫瘍細胞生物学教室
  • URL: http://www10.showa-u.ac.jp/~cancer/publication.htm
• [Remarks] 昭和大学薬学部生体分子薬学講座腫瘍細胞生物学部門ホームページ
  • URL: http://www10.showa-u.ac.jp/~cancer/publication%202013.htm
• [Remarks] Publications (昭和大学薬学部生体分子薬学講座腫瘍細胞生物学部門)
  • URL: http://www10.showa-u.ac.jp/~cancer/publication.htm