In the present study, 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. Here, DNER is linked to head and neck squamous cell carcinoma.