δ-Catenin is the only member of the p120 catenin (p120ctn) subfamily that its primary expression is restricted to the brain. Since δ-catenin is upregulated in human lung cancer, the effects of δ-catenin overexpression in lung cancer still need to be clarified. Immunohistochemistry was performed to investigate the expression of δ-catenin and Kaiso, a δ-catenin-binding transcription factor, in 151 lung cancer specimens. A correlation between cytoplasmic δ-catenin and Kaiso expression was also associated with high TNM stage, lymph node metastases and poor prognosis. Co-immunoprecipitation assay confirmed the interactions of δ-catenin and Kaiso in lung cancer cells. In addition, gene transfection and RNAi technology were used to demonstrate that increased δ-catenin expression was promoted, whereas its knockdown suppressed its lung cancer invasive ability. In addition, methylation-specific PCR and ChIP assay demonstrated that δ-catenin could regulate MTA2 via Kaiso in a methylation-dependent manner, while it could regulate cyclin D1 and MMP7 expression through Kaiso in a sequence-specific manner. In conclusion, a δ-catenin/Kaiso pathway exists in lung cancer cells. Increased δ-catenin expression is critical for maintenance of the malignant phenotype of lung cancer, making δ-catenin a candidate target protein for future cancer therapeutics. (Cancer Sci 2011; 102: 95–103)