SFRP1 (Secreted frizzled-related protein), a Wnt inhibitor, is downregulated in various human cancers. Cancer stem-like cells isolated from the Sfrp1 knock-out tumors showed higher tumorigenic potential. Molecular profiling on cancer stem cells revealed upregulation of epithelial to mesenchymal transition (EMT) markers, Akt, and also stem cell marker, Sox2. Importantly, inverse co-relation of Sfrp1 and Sox2 was observed in human oral and breast cancer patient samples. Epigenetic regulation of the Sfrp1 promoter leads to loss of Sfrp1, which is associated with poor survival in Skin and Oral cancer and promotes the enrichment of glycolysis and hypoxia in skin cancer stem cells (CSCs). Decitabine, a pharmacological drug that inhibits promoter hypermethylation of Sfrp1, thereby reducing tumorigenic, metastatic potential and metabolic rewiring in skin and oral squamous cell carcinoma CSCs.