Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis
Ok-Seon Kwon,
Eun-Ji Kwon,
Hyeon-Joon Kong,
Jeong-Yoon Choi,
Yun-Jeong Kim,
Eun-Woo Lee,
Wankyu Kim,
Haeseung Lee,
Hyuk-Jin Cha
Affiliations
Ok-Seon Kwon
Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
Eun-Ji Kwon
College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
Hyeon-Joon Kong
College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
Jeong-Yoon Choi
College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
Yun-Jeong Kim
College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
Eun-Woo Lee
Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
Wankyu Kim
Department of Life Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
Haeseung Lee
Department of Life Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea; Corresponding author. Intellectual Information Team, Future Medicine Division, Korea Institute of Oriental Medicine, Daejeon, 34054, Republic of Korea.
Hyuk-Jin Cha
College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea; Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea; Corresponding author. Research institute of pharmaceutical sciences, Seoul National University, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
Erastin, a synthetic lethal compound against cancer expressing an oncogenic RAS, inhibits cystine/glutamate antiporters and causes ferroptosis. However, despite recent evidence for the mechanisms underlying ferroptosis, molecular biomarkers of erastin-dependent ferroptosis have not been identified. Here, we employed isogenic lung cancer cell models to show that a redox imbalance leads to glutathione depletion and ferroptosis. Subsequent transcriptome analysis of pan-cancer cell lines revealed that the activity of transcription factors, including NRF2 and AhR, serve as important markers of erastin resistance. Based on the integrated expression of genes in the nuclear receptor meta-pathway (NRM), we constructed an NRM model and validated its robustness using an independent pharmacogenomics dataset. The NRM model was further evaluated by sensitivity tests on nine cancer cell lines for which erastin sensitivities had not been determined. Our pharmacogenomics approach has the potential to pave the way for the efficient classification of patients for therapeutic intervention using erastin.