MassIVE MSV000096356

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NRF2 supports non-small cell lung cancer growth independently of CBP/p300-enhanced glutathione synthesis

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Description

Nuclear factor erythroid 2-related factor 2 (NRF2) is a stress responsive transcription factor that is mutationally activated in a subset (~25%) of clinically-aggressive non-small cell lung cancers(NSCLC). Mechanistic insight into drivers of the NRF2 dependency remains poorly understood. Here, we defined a novel NRF2 target gene set linked to NRF2-dependency in cancer cell lines,and observed that a significant portion of these genes is devoid of promoter-proximal NRF2. Using integrated genomic analyses, we characterized extensive NRF2-dependent enhancer RNA (eRNA) synthesis and NRF2-mediated H3K27ac deposition at proximal and distal enhancer regions regulating these genes. While CBP/p300 is a well-validated direct interaction partner of NRF2 with prominent functions at enhancers, we report that this interaction is not required for NRF2-dependent NSCLC cell growth, indicating that NRF2 can sustain sufficient transcriptional activity in the absence of CBP/p300 coactivation. Broad metabolic profiling established a primary role for CBP/p300 in NRF2-dependent accumulation of glutathione and glutathione-related metabolites. While redox homeostasis via enhanced glutathione production is commonly associated with the normal physiological role of NRF2, collectively our results suggest that NRF2-dependent cancer cell growth does not require this enhanced glutathione production. [doi:10.25345/C5BC3T85G] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: NRF2 ; EP300 ; CBP ; A549 cell ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Scott Foster, Genentech, USA
Submitting User: psliu
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