bioRxiv preprint doi: https://doi.org/10.1101/459602; this version posted November 1, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer Authors: Yun Pyo Kang1, Laura Torrente1, Min Liu2, John M. Asara3,4, Christian C. Dibble5,6 and Gina M. DeNicola1,* Affiliations: 1 Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 2 Proteomics and Metabolomics Core Facility, Moffitt Cancer Center and Research Institute, Tampa, FL, USA 3 Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA, USA 4 Department of Medicine, Harvard Medical School, Boston, MA, USA 5 Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA 6 Department of Pathology, Harvard Medical School, Boston, MA, USA *Correspondence to:
[email protected]. Keywords: KEAP1, NRF2, cysteine, CDO1, sulfite Summary NRF2 is emerging as a major regulator of cellular metabolism. However, most studies have been performed in cancer cells, where co-occurring mutations and tumor selective pressures complicate the influence of NRF2 on metabolism. Here we use genetically engineered, non-transformed primary cells to isolate the most immediate effects of NRF2 on cellular metabolism. We find that NRF2 promotes the accumulation of intracellular cysteine and engages the cysteine homeostatic control mechanism mediated by cysteine dioxygenase 1 (CDO1), which catalyzes the irreversible metabolism of cysteine to cysteine sulfinic acid (CSA). Notably, CDO1 is preferentially silenced by promoter methylation in non-small cell lung cancers (NSCLC) harboring mutations in KEAP1, the negative regulator of NRF2.