In particular, DSG2, which is required to maintain the epithelial stability acting on cell-to-cell adhesion, targets PI3K/AKT, Hedgehog (Hh), and Wnt/β-catenin, which are widely implicated in human cancer and cancer cell models [45], as well as Sp1, a complex key transcription factor that acts on essential oncogenes, tumor suppressors, and housekeeping genes critical for the hallmarks of cancer. The gene discussed is SP1; the disease is cancer.