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A Super-Enhancer Driven by FOSL1 Controls miR-21-5p Expression in Head and Neck Squamous Cell Carcinoma
Yuehan Wan1,2, Rosalie G Hoyle3, Nan Xie2,4
1Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China.
Abstract:
MiR-21-5p is one of the most common oncogenic miRNAs that is upregulated in many solid cancers by inhibiting its target genes at the posttranscriptional level. However, the upstream regulatory mechanisms of miR-21-5p are still not well documented in cancers. Here, we identify a super-enhancer associated with the MIR21 gene (MIR21-SE) by analyzing the MIR21 genomic regulatory landscape in head and neck squamous cell carcinoma (HNSCC). We show that the MIR21-SE regulates miR-21-5p expression in different HNSCC cell lines and disruption of MIR21-SE inhibits miR-21-5p expression. We also identified that a key transcription factor, FOSL1 directly controls miR-21-5p expression by interacting with the MIR21-SE in HNSCC. Moreover, functional studies indicate that restoration of miR-21-5p partially abrogates FOSL1 depletion-mediated inhibition of cell proliferation and invasion. Clinical studies confirmed that miR-21-5p expression is positively correlated with FOSL1 expression. These findings suggest that FOSL1-SE drives miR-21-5p expression to promote malignant progression of HNSCC.
Insights
Researchers discovered that FOSL1, a transcription factor, drives the expression of miR-21-5p via a super-enhancer (MIR21-SE) in head and neck squamous cell carcinoma (HNSCC), promoting cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- MiR-21-5p is an oncogenic microRNA frequently upregulated in solid cancers, contributing to malignancy by post-transcriptional gene inhibition.
- The precise upstream regulatory mechanisms governing miR-21-5p expression in cancer remain incompletely understood.
Purpose of the Study:
- To elucidate the regulatory mechanisms controlling miR-21-5p expression in head and neck squamous cell carcinoma (HNSCC).
- To identify key factors and genomic elements involved in the upregulation of miR-21-5p in HNSCC.
Main Methods:
- Analysis of the MIR21 gene regulatory landscape in HNSCC to identify super-enhancers.
- Investigating the role of the identified MIR21 super-enhancer (MIR21-SE) in regulating miR-21-5p expression.
- Assessing the direct interaction of transcription factor FOSL1 with MIR21-SE and its effect on miR-21-5p.
- Functional studies to evaluate the impact of miR-21-5p restoration on FOSL1 depletion effects on cell proliferation and invasion.
- Clinical correlation analysis between miR-21-5p and FOSL1 expression levels in HNSCC patients.
Main Results:
- Identification of a super-enhancer (MIR21-SE) associated with the MIR21 gene in HNSCC.
- Demonstration that MIR21-SE regulates miR-21-5p expression, with its disruption leading to decreased miR-21-5p levels.
- Confirmation that FOSL1 directly controls miR-21-5p expression by interacting with MIR21-SE.
- Evidence that restored miR-21-5p partially rescues the inhibitory effects of FOSL1 depletion on HNSCC cell proliferation and invasion.
- Positive correlation observed between miR-21-5p and FOSL1 expression in clinical HNSCC samples.
Conclusions:
- FOSL1 directly drives miR-21-5p expression through the MIR21-SE in HNSCC.
- The FOSL1-SE axis promotes the malignant progression of HNSCC by upregulating miR-21-5p.
- Targeting the FOSL1-MIR21-SE pathway may offer a therapeutic strategy for HNSCC.
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