Super-enhancer-driven ITGA6 enhances stemness features of squamous cell carcinoma through stabilizing c-myc protein

Abstract Squamous cell carcinoma (SCC) is life-threatening malignancy. Cancer stem cells (CSCs) are associated with SCCs initiation, metastasis, therapy resistance, and relapse. Acquisition of super enhancer is a cause of hyper-activation of oncogenes in cancer, contributing to tumorigenesis and progression. In this study, we found disruption of SEs-associated transcription by BRD4 inhibitors JQ1 and I-BET151 inhibited the stemness features of SCC cells. Combined analysis with transcriptomics alterations induced by treatments of BRD4 inhibitors and SEs profile of SCC cells identified SEs-driven oncogenes in SCC cells. Among these SEs-driven oncogenes, ITGA6 (Integrin subunit α6) was highly expressed in SCC samples and predicted unfavorable prognosis in SCC patients. The ΔNp63α, a lineage-survival oncogene in SCC, enriched at ITGA6-SEs and was responsible for the activation of ITGA6-SEs. Silencing of ITGA6 substantially impeded the stemness features in vitro, as well as reduced thenumber of tumor-initiating cells of SCC in vivo. Mechanistically, silencing of ITGA6 resulted in the degradation of c-Myc protein via upregulation of an E3 ubiquitin ligase FBXO32. Furthermore, we demonstrated silencing of ITGA6 promoted nuclear translocation of YAP1, which facilitated TEAD1-mediated transcription of FBXO32 in SCC cells. Thus, our data suggested ITGA6 contributes to maintaining stemness features of SCC through a YAP1/FBXO32/c-myc cascade, providing a therapeutic target for eliminating cancer stem cells.