Oncogenic KRAS sensitizes lung adenocarcinoma to GSK-J4–induced metabolic and oxidative stress

Beom Jin Hong, Woo Yong Park, Hwa Ryeon Kim, Jin Woo Moon, Ho Yeon Lee, Jun Hyung Park, Seon Kyu Kim, Youngbin Oh, Jae Seok Roe, Mi Young Kim

Research output: Contribution to journalArticle

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, GSKJ4 reduced cellular levels of glutamate, a key source of the TCA cycle intermediate a-ketoglutarate (aKG) 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 wild-type 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.

Original languageEnglish
Pages (from-to)5849-5859
Number of pages11
JournalCancer Research
Volume79
Issue number22
DOIs
Publication statusPublished - 2019 Nov 15

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Physiological Stress
Oxidative Stress
Mutation
Histone Demethylases
Glutamic Acid
Glutathione
Neoplasms
Adenocarcinoma of lung
GSK-J4
cdc Genes
Glutamine
Epigenomics
Histones
Methylation
Cell Survival
Hypersensitivity
Down-Regulation
Antioxidants
Gene Expression

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Hong, B. J., Park, W. Y., Kim, H. R., Moon, J. W., Lee, H. Y., Park, J. H., ... Kim, M. Y. (2019). Oncogenic KRAS sensitizes lung adenocarcinoma to GSK-J4–induced metabolic and oxidative stress. Cancer Research, 79(22), 5849-5859. https://doi.org/10.1158/0008-5472.CAN-18-3511
Hong, Beom Jin ; Park, Woo Yong ; Kim, Hwa Ryeon ; Moon, Jin Woo ; Lee, Ho Yeon ; Park, Jun Hyung ; Kim, Seon Kyu ; Oh, Youngbin ; Roe, Jae Seok ; Kim, Mi Young. / Oncogenic KRAS sensitizes lung adenocarcinoma to GSK-J4–induced metabolic and oxidative stress. In: Cancer Research. 2019 ; Vol. 79, No. 22. pp. 5849-5859.
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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, GSKJ4 reduced cellular levels of glutamate, a key source of the TCA cycle intermediate a-ketoglutarate (aKG) 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 wild-type 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.",
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Hong, BJ, Park, WY, Kim, HR, Moon, JW, Lee, HY, Park, JH, Kim, SK, Oh, Y, Roe, JS & Kim, MY 2019, 'Oncogenic KRAS sensitizes lung adenocarcinoma to GSK-J4–induced metabolic and oxidative stress', Cancer Research, vol. 79, no. 22, pp. 5849-5859. https://doi.org/10.1158/0008-5472.CAN-18-3511

Oncogenic KRAS sensitizes lung adenocarcinoma to GSK-J4–induced metabolic and oxidative stress. / Hong, Beom Jin; Park, Woo Yong; Kim, Hwa Ryeon; Moon, Jin Woo; Lee, Ho Yeon; Park, Jun Hyung; Kim, Seon Kyu; Oh, Youngbin; Roe, Jae Seok; Kim, Mi Young.

In: Cancer Research, Vol. 79, No. 22, 15.11.2019, p. 5849-5859.

Research output: Contribution to journalArticle

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T1 - Oncogenic KRAS sensitizes lung adenocarcinoma to GSK-J4–induced metabolic and oxidative stress

AU - Hong, Beom Jin

AU - Park, Woo Yong

AU - Kim, Hwa Ryeon

AU - Moon, Jin Woo

AU - Lee, Ho Yeon

AU - Park, Jun Hyung

AU - Kim, Seon Kyu

AU - Oh, Youngbin

AU - Roe, Jae Seok

AU - Kim, Mi Young

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N2 - 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, GSKJ4 reduced cellular levels of glutamate, a key source of the TCA cycle intermediate a-ketoglutarate (aKG) 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 wild-type 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.

AB - 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, GSKJ4 reduced cellular levels of glutamate, a key source of the TCA cycle intermediate a-ketoglutarate (aKG) 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 wild-type 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.

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