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 journalArticlepeer-review

12 Citations (Scopus)

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

Bibliographical note

Funding Information:
We thank Drs. J. Massague for PC9, H2030, AsPC-1, and BxPC-3, G-.H. HA for HCC4006, D.S-LIM for WI38 and IMR90, J.-H. Cho for pBABE EGFR WT and EGFR L858R constructs, H.-S. Cheong for the pBABE KRASG12V mutant construct, and Z. Luo for pLenti-LKB1 construct. This work was supported by Ministry of Health & Welfare (HI17C2049), awarded to W.Y. Park; KIB CMCC (N1018001), KC30 (N11180008), NRF-2016M3A9B4915818, NRF-2019R1A2C2007207), Intelligent Synthetic Biology Center ISBC (2011-0031955), awarded to M.-Y. Kim; The Yonsei University Future-leading Research Initiative of 2018 (2018-22-0051), NRF grant funded by MSIT (NRF-2018R1C1B6003133), Brain Korea 21 Plus program, and the T.J. Park Science Fellowship, awarded to J.-S. Roe; BK21 Plus Program, and WISET funded by MSIT under the Program for Returners into R&D to H.-R. Kim.

Publisher Copyright:
©019 American Association for Cancer Research.

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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