In the future, cancer stem cell-based signaling perturbation therapies may be developed to downregulate stem cell transcription factors and/or histone methyltransferase, DOT1L (using Nanog/Oct4/Sox2/DOT1L-specific siRNA and shRNA vector approaches or DOT1L inhibitors) and/or to silence miR-10b (using anti-miR-10b inhibitor) for blocking HA/CD44v3-mediated Nanog/Oct4/Sox2 signaling and DOT1L/miR-10b expression/function as well as chemoresistance and HNSCC progression. Here, NANOG is linked to head and neck squamous cell carcinoma.