Thus, the aim of the present study was to assess the frequency of methylation of the selected negative regulators of Wnt signaling: CXXC4, DACT2, HDPR1 (DACT1), and FBXW11 and Shh signaling: HHIP, PTCH1, SUFU, ZIC1, and ZIC4 which were either rarely or never under study in head and neck cancers previously and correlate it with clinicopathological features in a group of HNSCC patients. Here, DACT2 is linked to head and neck squamous cell carcinoma.