Abstract
Cancer stem cells (CSCs) play a critical role in invasive growth and metastasis of human head and neck squamous cell carcinoma (HNSCC). Although significant progress has been made in understanding the self-renewal and pro-tumorigenic potentials of CSCs, a key challenge remains on how to eliminate CSCs and halt metastasis effectively. Here we show that super-enhancers (SEs) play a critical role in the transcription of cancer stemness genes as well as pro-metastatic genes, thereby controlling their tumorigenic potential and metastasis. Mechanistically, we find that bromodomain-containing protein 4 (BRD4) recruits Mediators and NF-κB p65 to form SEs at cancer stemness genes such as TP63, MET and FOSL1, in addition to oncogenic transcripts. In vivo lineage tracing reveals that disrupting SEs by BET inhibitors potently inhibited CSC self-renewal and eliminated CSCs in addition to elimination of proliferating non-stem tumor cells in a mouse model of HNSCC. Moreover, disrupting SEs also inhibits the invasive growth and lymph node metastasis of human CSCs isolated from human HNSCC. Taken together, our results suggest that targeting SEs may serve as an effective therapy for HNSCC by eliminating CSCs.
Highlights
Cancer stem cells (CSCs) play a critical role in invasive growth and metastasis of human head and neck squamous cell carcinoma (HNSCC)
Our study showed that SEs play a critical role in control of CSC self-renewal and pro-tumorigenic potentials
We showed that Bromo- and Extra-Terminal domain (BET) inhibitors potently eliminated both CSCs and rapidly proliferating cancer cells by disrupting SEs using in vivo lineage tracing
Summary
Cancer stem cells (CSCs) play a critical role in invasive growth and metastasis of human head and neck squamous cell carcinoma (HNSCC). In vivo lineage tracing reveals that disrupting SEs by BET inhibitors potently inhibited CSC self-renewal and eliminated CSCs in addition to elimination of proliferating non-stem tumor cells in a mouse model of HNSCC. We characterize SEs in SCC, and unexpectedly find that SEs uniquely controlled a set of cancer stemness-associated genes instead of MYC Using both a spontaneous mouse model and human patient-derived xenograft (PDX) model of HNSCC, we show that disrupting SEs by BET inhibitors effectively eliminated BMI1+ CSCs in addition to proliferating non-stem tumor cells, resulting in the inhibition of HNSCC invasive growth and metastasis
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