Oncogenic KRAS Sensitizes Lung Adenocarcinoma to GSK-J4-Induced Metabolic and Oxidative Stress

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dc.contributor.authorHong, Beom-Jinko
dc.contributor.authorPark, Woo-Yongko
dc.contributor.authorKim, Hwa-Ryeonko
dc.contributor.authorMoon, Jin Wooko
dc.contributor.authorLee, Ho Yeonko
dc.contributor.authorPark, Jun Hyungko
dc.contributor.authorKim, Seon-Kyuko
dc.contributor.authorOh, Youngbinko
dc.contributor.authorRoe, Jae-Seokko
dc.contributor.authorKim, Mi-Youngko
dc.date.accessioned2019-12-13T07:22:33Z-
dc.date.available2019-12-13T07:22:33Z-
dc.date.created2019-12-02-
dc.date.created2019-12-02-
dc.date.issued2019-11-
dc.identifier.citationCANCER RESEARCH, v.79, no.22, pp.5849 - 5859-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10203/268873-
dc.description.abstractGenetic and epigenetic changes (e.g., histone methylation) contribute to cancer development and progression, but our understanding of whether and how specific mutations affect a cancer's sensitivity to histone demethylase (KDM) inhibitors is limited. Here, we evaluated the effects of a panel of KDM inhibitors on lung adenocarcinomas (LuAC) with various mutations. Notably, LuAC lines harboring KRAS mutations showed hypersensitivity to the histone H3K27 demethylase inhibitor GSK-J4. Specifically, GSK-J4 treatment of KRAS mutant-containing LuAC downregulated cell-cycle progression genes with increased H3K27me3. In addition, GSK-J4 upregulated expression of genes involved in glutamine/glutamate transport and metabolism. In line with this, GSK-J4 reduced cellular levels of glutamate, a key source of the TCA cycle intermediate a-ketoglutarate (alpha KG) and of the antioxidant glutathione, leading to reduced cell viability. Supplementation with an aKG analogue or glutathione protected KRAS-mutant LuAC cells from GSK-J4-mediated reductions in viability, suggesting GSK-J4 exerts its anticancer effects by inducing metabolic and oxidative stress. Importantly, KRAS knockdown in mutant LuAC lines prevented GSK-J4-induced decrease in glutamate levels and reduced their susceptibility to GSK-J4, whereas overexpression of oncogenic KRAS in wildtype LuAC lines sensitized them to GSK-J4. Collectively, our study uncovers a novel association between a genetic mutation and KDM inhibitor sensitivity and identifies the underlying mechanisms. This suggests GSK-J4 as a potential treatment option for cancer patients with KRAS mutations. Significance: This study not only provides a novel association between KRAS mutation and GSK-J4 sensitivity but also demonstrates the underlying mechanisms, suggesting a potential use of GSK-J4 in cancer patients with KRAS mutations.-
dc.languageEnglish-
dc.publisherAMER ASSOC CANCER RESEARCH-
dc.titleOncogenic KRAS Sensitizes Lung Adenocarcinoma to GSK-J4-Induced Metabolic and Oxidative Stress-
dc.typeArticle-
dc.identifier.wosid000497329600017-
dc.identifier.scopusid2-s2.0-85075057702-
dc.type.rimsART-
dc.citation.volume79-
dc.citation.issue22-
dc.citation.beginningpage5849-
dc.citation.endingpage5859-
dc.citation.publicationnameCANCER RESEARCH-
dc.identifier.doi10.1158/0008-5472.CAN-18-3511-
dc.contributor.localauthorKim, Mi-Young-
dc.contributor.nonIdAuthorPark, Woo-Yong-
dc.contributor.nonIdAuthorKim, Hwa-Ryeon-
dc.contributor.nonIdAuthorLee, Ho Yeon-
dc.contributor.nonIdAuthorKim, Seon-Kyu-
dc.contributor.nonIdAuthorRoe, Jae-Seok-
dc.description.isOpenAccessN-
dc.type.journalArticleArticle-
dc.subject.keywordPlusCANCER-THERAPY-
dc.subject.keywordPlusINHIBITION-
dc.subject.keywordPlusCELLS-
dc.subject.keywordPlusTRANSCRIPTION-
dc.subject.keywordPlusDEMETHYLASES-
dc.subject.keywordPlusEPIGENETICS-
dc.subject.keywordPlusMETHYLATION-
dc.subject.keywordPlusGROWTH-
dc.subject.keywordPlusROLES-
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