Our efforts succeeded in identifying new S100A11 binding partners, desmosome proteins, which became a clue to uncover an essential part of S100A11 role within colorectal cancer cells; i.e., the desmosomal interaction of S100A11 regulates the expression of the desmosome component DSG1, activates the catenin-TCF signaling pathway via cytoplasmic release of γ-catenin, and is involved in the growth and migration of colorectal cancer. The gene discussed is HNF4A; the disease is colorectal cancer.