Here, we aimed at identifying suitable molecular targets for down-regulation of canonical Wnt signaling in HNSCC cells.<h4>Methods</h4>Candidate target genes (PORCN, WNT3A, FZD2, FZD5, LRP5, DVL1, CIP2A, SET, KDM1A, KDM4C, KDM6A, CBP, CARM1, KMT2A, TCF7, LEF1, PYGO1, XIAP) were silenced using siRNA and selected targets were subsequently blocked using small molecule inhibitors. Here, PYGO1 is linked to head and neck squamous cell carcinoma.