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

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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.
Publisher
AMER ASSOC CANCER RESEARCH
Issue Date
2019-11
Language
English
Article Type
Article
Citation

CANCER RESEARCH, v.79, no.22, pp.5849 - 5859

ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-18-3511
URI
http://hdl.handle.net/10203/268873
Appears in Collection
BS-Journal Papers(저널논문)
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