Previously, we discovered that FOSL1 facilitates the metastasis of head and neck squamous cell carcinoma (HNSCC) cancer stem cells in a spontaneous mouse model. However, the molecular mechanisms remained unclear. Here, we demonstrated that FOSL1 serves as the dominate AP1 family member and is significantly upregulated in HNSCC tumor tissues and correlated with metastasis of HNSCC. Mechanistically, FOSL1 exerts its function in promoting tumorigenicity and metastasis predominantly via selective association with Mediators to establish super-enhancers (SEs) at a cohort of cancer stemness and pro-metastatic genes, such as SNAI2 and FOSL1 itself. Depletion of FOSL1 led to disruption of SEs and expression inhibition of these key oncogenes, which resulted in the suppression of tumor-initiation and metastasis. We also revealed that the abundance of FOSL1 is positively associated with the abundance of SNAI2 in HNSCC and the high expression of FOSL1 and SNAI2 levels are associated with short overall disease-free survival. Finally, the administration of the FOSL1 inhibitor, SR11302, significantly suppressed tumor growth and lymph node metastasis of HNSCC in a patient-derived-xenograft model. These findings indicate that FOSL1 is a master regulator that promotes the metastasis of HNSCC through a SE-driven transcription program that may represent an attractive target for therapeutic interventions.
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