头颈部鳞状细胞癌
转移
癌症研究
医学
增强子
癌症
癌症干细胞
转录因子
生物
头颈部癌
内科学
基因
遗传学
作者
Ming Zhang,Rosalie G. Hoyle,Zhikun Ma,Bo Sun,Wenli Cai,Hao Cai,Ning Xie,Yadong Zhang,Jinsong Hou,Xiqiang Liu,Demeng Chen,Glen E. Kellogg,Hisashi Harada,Yue Sun,Cheng Wang,Jiong Li
标识
DOI:10.1016/j.ymthe.2021.03.024
摘要
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 dominant activating protein 1 (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 levels of FOSL1 and SNAI2 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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