Analysis of molecular mechanisms to promote epigenomic disturbances and oncogenic transformation by histone H2A mutants

Research Project

Project/Area Number	16K07201
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Genome biology
Research Institution	The University of Tokushima (2018) Kyushu University (2017) Nagasaki University (2016)
Principal Investigator	AIBARA Hitoshi 徳島大学, 先端酵素学研究所(プロテオ), 特任助教 (80587717)
Project Period (FY)	2016-04-01 – 2019-03-31
Project Status	Completed (Fiscal Year 2018)
Budget Amount *help	¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000) Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000) Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000) Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords	クロマチン / ヒストン修飾 / がん / ゲノム
Outline of Final Research Achievements	The C-terminal region of histone H2A is phosphorylated or ubiquitylated in human cancer cell lines. Previous our study has demonstrated that VRK1 kinase phoaphorylates threonine 120 in H2A (H2A-T120) on the core promoter region of the cyclin oD1 gene which is a master regulator of cell proliferation. VRK1 knockdown showed loss of H2A-T120 phosphorylation and increased ubiquitylation of lysine 119 in H2A (H2A-K119). In vitro studies demonstrated that H2A-T120 phosphorylation and H2A-K119 ubiquitylation were mutually inhibitory. Furthermore, expression of phospho-mimic mutant of H2A (H2A-T120D) transformed NIH/3T3 cells. Finally, utilizing COSMIC database, we identified several missence mutations of H2A-K118, K119, T120 that exhibited tumorigenic activities. These results suggest that bankruptcy of balance between H2A-T120 phosphorylation and H2A-K118, K119 ubiquitylation causes inappropriate gene expression, including upregulated cyclin D1, which promotes oncogenic transformation.
Academic Significance and Societal Importance of the Research Achievements	ヒストン修飾酵素の発現異常、遺伝子増幅、ナンセンス・ミスセンス変異と細胞癌化の直接的な関連性は多数報告されているが、ヒストン自体の変異が癌化に関連する報告は、典型的なヒストンH3に対して存在比わずか１％のバリアントH3.3のケースの2例のみである。この変異は、小児神経膠腫の高グレードで顕在し、有効な治療法確立の標的あるいは突破口になる可能性があり注目度は高い。それに対し本研究は、バリアントでない典型的H2A変異を見出したこと、H2Aのリン酸化およびユビキチン化部位の変異が癌化を誘発することを初めて示している。将来的なエピゲノム修正・調節による癌治療の礎となることが期待される。