A Tumor-Protective Role for Human Kallikrein-Related Peptidase 6 in Breast Cancer Mediated by Inhibition of Epithelial-to-Mesenchymal Transition

摘要: Human kallikrein-related peptidase 6 (KLK6) was cloned as a putative class II tumor suppressor based on its inactivated expression in metastatic breast cancer. Here, we investigated the mechanism(s) underlying silencing of KLK6 gene cancer and implications for progression. We present evidence that tumor-specific loss is due to hypermethylation specific CpGs located proximal promoter. Methylation-dependent binding methyl CpG-binding protein 2 formation repressive chromatin mediated by localized histone deacetylation are critical components tumors. Re-expression nonexpressing MDA-MB-231 cells stable cDNA transfection resulted marked reversal their malignant phenotype, manifested lower proliferation rates saturation density, inhibition anchorage-independent growth, reduced cell motility, dramatically ability form tumors when implanted severe combined immunodeficiency mice. Interestingly, growth observed at physiologic concentrations KLK6, but not highly overexpressed, subset Differential proteomic profiling revealed re-expression results significant down-regulation vimentin which represents an established marker epithelial-to-mesenchymal transition concomitant up-regulation calreticulin epithelial markers cytokeratin 8 19, indicating may play protective role against progression likely transition. suggest epigenetically regulated human provide ways pharmacologic modulation.