Identification of nutrients to control rRNA transcription through epigenetic regulation by KDM2A in rDNA promoter.

2020 Fiscal Year Final Research Report

• Project/Area Number: 17K07798
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Food science
• Research Institution: Takasaki University of Health and Welfare
• Principal Investigator: Yuji Tanaka 高崎健康福祉大学, 薬学部, 講師 (90453422)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Keywords: KDM2A / リボソームRNA / メトホルミン / 没食子酸 / AMPK / コハク酸 / ROS / 転写

Outline of Final Research Achievements

K-demethylase 2A (KDM2A) is a specific demethylase for histone H3K36me1/2. We previously demonstrated that KDM2A demethylases H3K36me2 in ribosomal DNA (rDNA) promoter to reduce ribosomal RNA (rRNA) transcription in response to starvation. In this study, we screened chemical-mini library to identify compound to control KDM2A activity. We found that KDM2A activity was induced by metformin, a drug for type 2 diabetes, in MCF-7 cells. The activation of AMPK and reduction of intracellular succinate by 2.5 mM metformin treatments were required in KDM2A activation.
Gallic acid was also identified as KDM2A activator from that screening. The activation of AMPK and the production of reactive oxygen species by 50 μM gallic acid treatments in MCF-7 cells. These observations suggest that the cellular condition such as energy, metabolic, and redox status, which were supplied by nutrients, converge in KDM2A to control rRNA transcription mediated by histone demethylation in the rDNA promoter.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

本結果は糖尿病治療薬であるメトホルミンにKDM2Aを通じた抗がん的作用発揮の可能性を示すもので、既存薬の新しい作用側面を示唆するものである。また、細胞内代謝変動によってrRNA転写が制御される際、代謝中間体そのものがエピゲノムに作用できる事を示唆している。この点は代謝異常応答で中間体分子そのものが伝達物質として働く局面を示唆している。また、没食子酸によるエピゲノム制御はあまり解析されていないが、本結果は特定の食品添加物や栄養素がエピゲノム制御に関わる事を示しており、こうした作用が発揮できる化合物が他にも存在する事を想起させる。