Intermediary filaments play a crucial role in transformation of cells to a malignant phenotype. Here, we report that tumor suppressor SMAR1 downregulates Cytokeratin 8 gene expression by modulating p53-mediated transactivation of this gene. Moreover, the cell surface cytokeratin expression was downregulated leading to a decreased migration and invasiveness of cells. We further validated these results using genotoxic stress agents that lead to an increase in the levels of SMAR1 protein. This subsequently represses the transcription of Cytokeratin 8 gene by local chromatin condensation mediated by histone methylation and deacetylation. Evaluation of SMAR1 and Cytokeratin 8 proteins in different grades of cancer using tissue microarray point out at the inverse expression profiles of these genes (i.e. low levels of SMAR1 correlating with high expression of Cytokeratin 8) in higher grades of breast cancer. Therefore, the results presented here highlight the mechanism of Cytokeratin 8 gene regulation by interplay of tumor suppressor proteins SMAR1 and p53.