2021 Fiscal Year Final Research Report
Mechanism of gene expression via epigenetic regulation by HSF1 complex
| Project/Area Number |
19K06490
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 43010:Molecular biology-related
|
|---|
| Research Institution | Yamaguchi University |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2019-04-01 – 2022-03-31
|
| Keywords | HSF1 / TRRAP / TIP60 / TRIM33 / PLK1 / メラノーマ細胞 |
|---|
| Outline of Final Research Achievements |
I demonstrate that HSF1 recruits the TRRAP-TIP60 acetyltransferase complex in HSP70 promoter during heat shock in a manner dependent on phosphorylation of HSF1-S419. TRIM33 recruited to the promoter by interactions with HSF1 and an TIP60-mediated acetylation mark, and cooperated with the related factor TRIM24 for mono-ubiquitination of histone H2B on K120. These changes in histone modifications are triggered by phosphorylation of HSF1-S419 via PLK1, and stabilize the HSF1-transcription complex in HSP70 promoter. Furthermore, the HSF1-S419 phosphorylation is constitutively enhanced in and promotes proliferation of melanoma cells. Our results provide novel mechanisms for HSF1 phosphorylation-dependent establishment of an active chromatin status, which is important for tumorigenesis.
|
| Free Research Field |
分子細胞生物学
|
| Academic Significance and Societal Importance of the Research Achievements |
本研究で、HSF1-TRRAP-TIP60複合体が、HSF1結合領域周辺のクロマチン修飾を変化させ、がん細胞の増殖に関与することを明らかにした。この複合体形成はHSF1のS419リン酸化に依存した。さらに、マウスを用いた実験から、この複合体の形成阻害するHSF1-S419変異体はメラノーマ細胞の腫瘍形成を顕著に抑制することを明らかにした。よって、HSF1-TRRAP-TIP60複合体の解析から、腫瘍形成に重要なHSF1リン酸化依存的な活性型クロマチン状態の確立の新規メカニズムを提供し、このメカニズムをターゲットとした新たな治療薬の開発に結びつく可能性がある。
|
