ARID1A loss is associated with increased NRF2 signaling in human head and neck squamous cell carcinomas
Public Deposited- Creator
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Nguyen V.
- Affiliation: School of Medicine, Curriculum in Toxicology
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Schrank T.P.
- Affiliation: School of Medicine, Department of Otolaryngology/Head and Neck Surgery
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Major M.B.
- Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
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Weissman B.E.
- Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
- Abstract
- Prior to the next generation sequencing and characterization of the tumor genome landscape, mutations in the SWI/SNF chromatin remodeling complex and the KEAP1-NRF2 signaling pathway were underappreciated. While these two classes of mutations appeared to independently contribute to tumor development, recent reports have demonstrated a mechanistic link between these two regulatory mechanisms in specific cancer types and cell models. In this work, we expand upon these data by exploring the relationship between mutations in BAF and PBAF subunits of the SWI/SNF complex and activation of NRF2 signal transduction across many cancer types. ARID1A/B mutations were strongly associated with NRF2 transcriptional activity in head and neck squamous carcinomas (HNSC). Many additional tumor types showed significant association between NRF2 signaling and mutation of specific components of the SWI/SNF complex. Different effects of BAF and PBAF mutations on the polarity of NRF2 signaling were observed. Overall, our results support a context-dependent functional link between SWI/SNF and NRF2 mutations across human cancers and implicate ARID1A inactivation in HPV-negative HNSC in promoting tumor progression and survival through activation of the KEAP1-NRF2 signaling pathway. The tumorspecific effects of these mutations open a new area of study for how mutations in the KEAP1-NRF2 pathway and the SWI/SNF complex contribute to cancer.
- Date of publication
- 2024
- Keyword
- ARID1A gene
- Mutation
- NF-E2-Related Factor 2
- gene
- RNA sequencing
- signal transduction
- proteomics
- mutation
- gene loss
- Article
- metabolism
- barrier to autointegration factor
- cullin
- ARID1B gene
- human
- head and neck tumor
- genetics
- transcription factor SNF
- head and neck squamous cell carcinoma
- Squamous Cell Carcinoma of Head and Neck
- Head and Neck Neoplasms
- Signal Transduction
- ARID1A protein, human
- mutation rate
- transcriptomics
- whole genome sequencing
- DNA binding protein
- nuclear protein
- copy number variation
- transcription factor
- protein SWI
- gene expression
- somatic mutation
- whole exome sequencing
- kelch like ECH associated protein 1
- human tissue
- gene set enrichment analysis
- Nuclear Proteins
- differential gene expression
- Kelch-Like ECH-Associated Protein 1
- TMT labeling
- PBRM1 gene
- Nrf2 signaling
- Transcription Factors
- Humans
- transcription factor Nrf2
- signal noise ratio
- DNA sequencing
- ARID2 gene
- DNA-Binding Proteins
- controlled study
- DOI
- Identifier
- Resource type
- Article
- Rights statement
- In Copyright
- License
- Attribution 4.0 International
- Journal title
- PLoS ONE
- Journal volume
- 19
- Journal issue
- 2-Feb
- Language
- English
- Version
- Publisher
- Funder
- National Institute of Environmental Health Sciences, NIEHS, (T32 ES007126)
- National Cancer Institute, NCI, (R01 CA216051)
- National Institute of Dental and Craniofacial Research, NIDCR, (K08 DE029241)
- ISSN
- 1932-6203
- Publisher
- Public Library of Science
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