A Super-Enhancer Driven by FOSL1 Controls miR-21-5p Expression in Head and Neck Squamous Cell Carcinoma

  • Front Oncol. 2021 Apr 16;11:656628. doi: 10.3389/fonc.2021.656628.
Yuehan Wan  1  2 ,  Rosalie G Hoyle  3 ,  Nan Xie  2  4 ,  Wenjin Wang  1  2 ,  Hongshi Cai  1  2 ,  Ming Zhang  1  2 ,  Zhikun Ma  3 ,  Gan Xiong  1  2 ,  Xiuyun Xu  1  2 ,  Zhengxian Huang  1  2 ,  Xiqiang Liu  5 ,  Jiong Li  3  6 ,  Cheng Wang  1  2
Affiliations
  • 1. Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China.
  • 2. Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, China.
  • 3. Department of Medicinal Chemistry, Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy and the Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States.
  • 4. Department of Oral Pathology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, China.
  • 5. Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 6. Department of Oral and Craniofacial Molecular Biology, Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University, Richmond, VA, United States.
PMID: 33937067 DOI: 10.3389/fonc.2021.656628
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.

Keywords
FOSL1; head and neck squamous cell carcinoma; metastasis; miR-21-5p; super enhancer.
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