DC Field | Value | Language |
---|---|---|
dc.contributor.author | Hong, Beom-Jin | ko |
dc.contributor.author | Park, Woo-Yong | ko |
dc.contributor.author | Kim, Hwa-Ryeon | ko |
dc.contributor.author | Moon, Jin Woo | ko |
dc.contributor.author | Lee, Ho Yeon | ko |
dc.contributor.author | Park, Jun Hyung | ko |
dc.contributor.author | Kim, Seon-Kyu | ko |
dc.contributor.author | Oh, Youngbin | ko |
dc.contributor.author | Roe, Jae-Seok | ko |
dc.contributor.author | Kim, Mi-Young | ko |
dc.date.accessioned | 2019-12-13T07:22:33Z | - |
dc.date.available | 2019-12-13T07:22:33Z | - |
dc.date.created | 2019-12-02 | - |
dc.date.created | 2019-12-02 | - |
dc.date.issued | 2019-11 | - |
dc.identifier.citation | CANCER RESEARCH, v.79, no.22, pp.5849 - 5859 | - |
dc.identifier.issn | 0008-5472 | - |
dc.identifier.uri | http://hdl.handle.net/10203/268873 | - |
dc.description.abstract | Genetic 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.language | English | - |
dc.publisher | AMER ASSOC CANCER RESEARCH | - |
dc.title | Oncogenic KRAS Sensitizes Lung Adenocarcinoma to GSK-J4-Induced Metabolic and Oxidative Stress | - |
dc.type | Article | - |
dc.identifier.wosid | 000497329600017 | - |
dc.identifier.scopusid | 2-s2.0-85075057702 | - |
dc.type.rims | ART | - |
dc.citation.volume | 79 | - |
dc.citation.issue | 22 | - |
dc.citation.beginningpage | 5849 | - |
dc.citation.endingpage | 5859 | - |
dc.citation.publicationname | CANCER RESEARCH | - |
dc.identifier.doi | 10.1158/0008-5472.CAN-18-3511 | - |
dc.contributor.localauthor | Kim, Mi-Young | - |
dc.contributor.nonIdAuthor | Park, Woo-Yong | - |
dc.contributor.nonIdAuthor | Kim, Hwa-Ryeon | - |
dc.contributor.nonIdAuthor | Lee, Ho Yeon | - |
dc.contributor.nonIdAuthor | Kim, Seon-Kyu | - |
dc.contributor.nonIdAuthor | Roe, Jae-Seok | - |
dc.description.isOpenAccess | N | - |
dc.type.journalArticle | Article | - |
dc.subject.keywordPlus | CANCER-THERAPY | - |
dc.subject.keywordPlus | INHIBITION | - |
dc.subject.keywordPlus | CELLS | - |
dc.subject.keywordPlus | TRANSCRIPTION | - |
dc.subject.keywordPlus | DEMETHYLASES | - |
dc.subject.keywordPlus | EPIGENETICS | - |
dc.subject.keywordPlus | METHYLATION | - |
dc.subject.keywordPlus | GROWTH | - |
dc.subject.keywordPlus | ROLES | - |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.