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Updated: Jul 3, 2025
Isolation and Characterization of a Head and Neck Squamous Cell Carcinoma Subpopulation Having Stem Cell Characteristics
Published on: May 11, 2016
ARID1A loss is associated with increased NRF2 signaling in human head and neck squamous cell carcinomas
Vinh Nguyen1,2, Travis P Schrank1,3, Michael B Major1,4
1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America.
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 tumor-specific 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.
Insights
Mutations in SWI/SNF complexes and the KEAP1-NRF2 pathway are linked in cancers. ARID1A inactivation in head and neck cancers activates NRF2 signaling, promoting tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Mutations in the SWI/SNF chromatin remodeling complex and the KEAP1-NRF2 signaling pathway were historically underestimated in cancer.
- Recent studies suggest a mechanistic link between these two pathways in specific cancer types.
Purpose of the Study:
- To investigate the relationship between SWI/SNF complex mutations (BAF and PBAF subunits) and NRF2 signaling activation across diverse cancer types.
- To explore the specific role of ARID1A/B mutations in head and neck squamous cell carcinomas (HNSC) and their association with NRF2 activity.
Main Methods:
- Analysis of genomic data to identify mutations in SWI/SNF subunits and assess NRF2 transcriptional activity.
- Comparative analysis of BAF and PBAF mutations' effects on NRF2 signaling polarity.
- Focus on HPV-negative HNSC to examine ARID1A inactivation's impact.
Main Results:
- ARID1A/B mutations showed a strong association with NRF2 transcriptional activity in HNSC.
- Significant correlations between NRF2 signaling and SWI/SNF component mutations were observed in multiple tumor types.
- BAF and PBAF mutations exhibited distinct effects on NRF2 signaling polarity.
Conclusions:
- A context-dependent functional link exists between SWI/SNF and NRF2 mutations in human cancers.
- ARID1A inactivation in HPV-negative HNSC promotes tumor progression and survival via KEAP1-NRF2 pathway activation.
- These findings open new avenues for studying the interplay of SWI/SNF and KEAP1-NRF2 pathway mutations in cancer development.
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