Molecular mechanisms underlying the epigenetic dysregulation by synovial sarcoma specific fusion oncoprotein

• Project/Area Number: 25670643
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Orthopaedic surgery
• Research Institution: Kyoto University
• Principal Investigator: KATO Tomohisa 京都大学, 再生医科学研究所, 講師 (50301247)
• Co-Investigator(Kenkyū-buntansha): TOGUCHIDA Junya 京都大学, 再生医科学研究所, 教授 (40273502)
• Project Period (FY): 2013-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2013: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: 滑膜肉腫 / エピジェネティクス / 遺伝子発現制御 / クロマチン修飾 / タンパク質間相互作用 / がんの起源細胞

Research Abstract

We have been trying to unravel the molecular mechanism underlying the transcriptional dysregulation of FZD10 gene in synovial sarcomas (SSs) and have found that histone acetylation of the promoter region of FZD10 strongly correlates with up-regulation of FZD10 in SS. So, we next aimed to identify the histone acetyltransferase (HAT) responsible for this. By adopting pull-down assay followed by Western blotting, we succeeded to identify two HATs (designated as SSIH1 and 2) as the interactors of SS18-SSX. Furthermore, by using dominant-negative (DN) forms of SSIH1 and SSIH2, we have demonstrated that ectopic expression of SSIH(DN) in SS cells abrogated the expression of FZD10. This result indicates SSIH1 and SSIH2 are functionally involved in up-regulation of FZD10 in SSs, However, ChIP assay revealed that only SSHI1 occupies the FZD10 promoter region in vivo. Collectively, We have identified SSIH1 as the HAT responsible for the FZD10 dysregulation in SSs.

Research Products

• [Journal Article] AFAP1L1, a novel associating partner with vinculin, modulates cellular morphology and motility, and promotes the progression of colorectal cancers. (2014)
  • Author(s): Takahashi R, Nagayama S, Furu M, Kajita Y, Jin Y, Kato T, Imoto S, Sakai Y, Toguchida J.
  • Journal Title: Cancer Medicine Volume: なし Issue: 4 Pages: 759-774
  • DOI: 10.1002/cam4.237
  • Peer Reviewed
• [Presentation] SS18-SSX is a cell-context-dependent epigenetic regulator : implication for cell-of-origin of synovial sarcomas (2013)
  • Author(s): Sakura Tamaki, Makoto Fukuta, Kazuo Hayakawa, Tomohisa Kato, Junya Toguchida
  • Organizer: 18th Annual Meeting of the Connective Tissue Oncology Society
  • Place of Presentation: New York
  • Year and Date: 2013-10-31
• [Presentation] 滑膜肉腫原因遺伝子産物 SS18-SSXの相互作用因子の同定によるエピジェネティクス制御破錠の分子基盤の解明 (2013)
  • Author(s): 加藤友久、玉置さくら、早川和男、福田誠、岡本健、戸口田淳也
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2013-10-04
• [Presentation] 細胞背景は滑膜肉腫特異的融合タンパクSYT-SSXのエピジェネティック制御において重要な因子である (2013)
  • Author(s): 玉置さくら、加藤友久、早川和男、福田誠、高原直子、岡本健、戸口田淳也
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2013-10-04
• [Presentation] 滑膜肉腫原因融合遺伝子産物 SS18-SSX の相互作用因子の同定によるエピジェネティクス制御破錠の分子基盤の解明
  • Author(s): 加藤友久、玉置さくら、早川和男、福田誠、岡本健、戸口田淳也
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] 細胞背景は滑膜肉腫特異的融合タンパク SYT-SSX のエピジェネティック制御において重要な因子である
  • Author(s): 玉置さくら、加藤友久、早川和男、福田誠、高原直子、岡本健、戸口田淳也
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] SS18-SSX IS A CELL-CONTEXT-DEPEDENT EPIGENETIC REGULATOR:
  • Author(s): Sakura Tamaki, Makoto Fukuta, Kazuo Hayakawa, Tomohisa Kato, Junya Toguchida
  • Organizer: Connective Tissue Oncology Society 18th Annual Meeting
  • Place of Presentation: Sheraton Times Square New York（USA）