Because there is no changes of methylation levels in the CpG island of APC, Axin, and β-catenin genes in OSCC (Shiah et al., 2016), downregulation of Wnt signaling in OSCC and HNSCC is usually due to methylation of different Wnt pathway inhibitors, such as SFRP-2, WIF-1, DKK-1 (Katase et al., 2010), Dachshund family transcription factor 1 (DACH1), and RUNT-related transcription factor 3 (RUNX3). Here, RUNX3 is linked to head and neck squamous cell carcinoma.