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.
Bibliographical noteFunding 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.
©019 American Association for Cancer Research.
All Science Journal Classification (ASJC) codes
- Cancer Research