We found that knockdown of DSG3 in cancer cells resulted in (1) disruption of its interaction with plakoglobin and induced plakoglobin translocation from the cell membrane to the nucleus (Figure 1), (2) an increase in the interaction of plakoglobin with the TCF transcriptional factor and suppressed the TCF/LEF transcriptional activity (Figures 2, 3), (3) inhibition of the expression of TCF/LEF downstream target genes c-myc, cyclin D1, and MMP-7 (Figures 3, 5), and (4) suppression of the malignant phenotypes, including cell proliferation, invasion, and tumor growth (Figures 4, 5). The gene discussed is HNF4A; the disease is neoplasm.