Summary of Study ST003623
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002208. The data can be accessed directly via it's Project DOI: 10.21228/M86Z6P This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.
| Study ID | ST003623 |
| Study Title | NRF2 supports non-small cell lung cancer growth independently of CBP/p300-enhanced glutathione synthesis: Global metabolomics analysis on A549 cells at different NRF2 status (Part 1 of 3) |
| Study Type | Untargeted Metabolomics |
| Study Summary | This study aims at discovering metabolic changes in A549 cancer cells in the presence and absence of NRF2, and a mutant NRF2 genotypes. Metabolites were extracted from cell pellets by using an LLE method with Methanol/Chloroform/water. The aqueous layer was analyzed by HILIC-HRMS. An in-house RT library was used to identify metabolites. Statistical analyses was performed to identify statistically significant changes in the metabolism. 35 metabolites presented differential abundance between NRF2 knockdown and wildtype conditions. In particular, GSH and several glutamate dipeptides were significantly depleted upon NRF2 knockdown, in line with the prevailing role of NRF2 in controlling GSH biosynthesis. Disruption of additional metabolites involved in the PPP (sedoheptulose-7-phosphate, S7P), nucleotide (CMP, IMP) and amino acid (kynurenine, homocitrulline) metabolism were also observed upon NRF2 knockdown. |
| Institute | Genentech Inc. |
| Last Name | Wang |
| First Name | Mike |
| Address | 1 DNA Way, South San Francisco, CA 94080, USA |
| wang.mike@gene.com | |
| Phone | 6502457991 |
| Submit Date | 2024-12-06 |
| Raw Data Available | Yes |
| Raw Data File Type(s) | mzML |
| Analysis Type Detail | LC-MS |
| Release Date | 2025-01-02 |
| Release Version | 1 |
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Project:
| Project ID: | PR002208 |
| Project DOI: | doi: 10.21228/M86Z6P |
| Project Title: | NRF2 supports non-small cell lung cancer growth independently of CBP/p300-enhanced glutathione synthesis |
| Project Type: | MS quantitative analysis |
| Project Summary: | 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. |
| Institute: | Genentech Inc. |
| Last Name: | Wong |
| First Name: | Weng Ruh |
| Address: | 1 DNA Way, South San Francisco, CA 94080, USA |
| Email: | wongw24@gene.com |
| Phone: | 4089048962 |
| Contributors: | Ryan J. Conrad, James A. Mondo, Mike Lingjue Wang, Peter S. Liu, Zijuan Lai, Feroza K Choudhury, Qingling Li, Weng Ruh Wong, James Lee, Frances Shanahan, Eva Lin, Scott Martin, Joachim Rudolph, John G. Moffat, Dewakar Sangaraju, Wendy Sandoval, Timothy Sterne-Weiler, Scott A. Foster |
