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α-ketoglutarate suppresses immediate early gene expression in cancer cells

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Author(s)
Sungmin JooSeungwoo BaekJaehyeon KangDong Soo SeoTaeg Kyu KwonYounghoon Jang
Keimyung Author(s)
Kwon, Taeg Kyu
Department
Dept. of Immunology (면역학)
Journal Title
Biochem Biophys Res Commun
Issued Date
2022
Volume
637
Keyword
Cancer cellsGLS inhibitorIEGNR4AαKG
Abstract
Cancer cells exhibit increased glutamine consumption compared to normal cells, supporting cell survival and proliferation. Glutamine is converted to α-ketoglutarate (αKG), which then enters the tricarboxylic acid cycle to generate ATP. Recently, therapeutic modulation of glutamine metabolism has become an attractive metabolic anti-cancer strategy. However, how synergistic combination therapy is required to overcome glutamine metabolism drug resistance remains elusive. To address this issue, we first investigated the role of αKG in regulating gene expression in several cancer cell lines. Using RNA-seq analysis and histone modification screening, we demonstrated that αKG reduced the expression of the immediate early gene (IEG) in cancer cells in an H3K27 acetylation-dependent manner. Conversely, glutaminase (GLS) inhibitors induce IEG expression in cancer cells. Furthermore, we showed that siRNA knockdown of orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) induces IEG expression. Notably, the NR4A1 agonist cytosporone B sensitizes GLS inhibitor resistance to cancer cell death. Together, these findings indicate that therapeutic targeting of IEG dysregulation by αKG can be a potentially effective anti-cancer therapeutic strategy for glutamine metabolism inhibitors.
Keimyung Author(s)(Kor)
권택규
Publisher
School of Medicine (의과대학)
Type
Article
ISSN
1090-2104
Source
https://www.sciencedirect.com/science/article/pii/S0006291X22015625?via%3Dihub
DOI
10.1016/j.bbrc.2022.11.021
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/44740
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
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