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

Yuehan Wan; Rosalie G Hoyle; Nan Xie; Wenjin Wang; Hongshi Cai; Ming Zhang; Zhikun Ma; Gan Xiong; Xiuyun Xu; Zhengxian Huang; Xiqiang Liu; Jiong Li; Cheng Wang

doi:10.3389/fonc.2021.656628

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. eCollection 2021.

Authors

Yuehan Wan^{1

2}, Rosalie G Hoyle³, Nan Xie^{2

4}, Wenjin Wang^{1

2}, Hongshi Cai^{1

2}, Ming Zhang^{1

2}, Zhikun Ma³, Gan Xiong^{1

2}, Xiuyun Xu^{1

2}, Zhengxian Huang^{1

2}, Xiqiang Liu⁵, 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.

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.