| Project/Area Number |
18K15227
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | Japanese Foundation for Cancer Research |
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Principal Investigator |
Yoshino Seiko 公益財団法人がん研究会, がん研究所 発がん研究部, 研究員 (40793617)
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | Trib1 / Hoxa9 / C/EBPα / ChIP-seq / 白血病 |
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| Outline of Final Research Achievements |
The pseudokinase Trib1 functions as a myeloid oncogene that recruits the ubiquitin ligase COP1 to C/EBPα and interacts with MEK1 to enhance ERK phosphorylation. Close genetic interaction between Trib1 and Hoxa9 have been observed in myeloid leukemogenesis. Herein, we provide evidence that Trib1 modulates Hoxa9-associated super-enhancers. ChIP-seq analysis identified increased H3K27Ac signals at super-enhancers of the Erg, Spns2, Rgl1, and Pik3cd loci, as well as increased mRNA expression. Modification of super-enhancer activity was mostly achieved via p42-specific degradation of C/EBPα by Trib1. Silencing of Erg abrogated the growth advantage acquired by Trib1 overexpression, indicating that Erg is a critical downstream target. Moreover, treatment with a BRD4 inhibitor JQ1 showed growth inhibition in a Trib1/Erg-dependent manner both in vitro and in vivo. Collectively, our study demonstrates a novel mechanism of Trib1 in modulations of chromatin and Hoxa9-driven transcription.
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| Academic Significance and Societal Importance of the Research Achievements |
Trib1は、野生型の骨髄幹／前駆細胞での過剰発現だけで細胞の不死化とin vivoでの白血病誘導能を示す数少ない白血病原因遺伝子である。本研究は、Trib1を軸として、これまで繋がりが見えなかったHoxa9とC/EBPαのクロストークを明らかにした。さらに、本研究で同定した、Trib1/Hoxa9標的遺伝子が、新たな治療標的やバイオマーカーの発見に結びつくことが期待できる。
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