p53 down-regulates SETDB1 gene expression during paclitaxel induced-cell death.

Paclitaxel (PTX) is a chemotherapeutic drug which induces tubulin stability and regulates expression of death related genes in human cancer cells. Its anticancer mechanism is well known, however its effects on chromatin remodeling factors are poorly understood. In this study, we examine if PTX affects expression of SETDB1 HMTase during cell death. PTX induces cell death via G2/M arrest in human lung cancer cells. PTX treatment induces the p53 protein, but down-regulates expression of SETDB1 at the transcriptional level as well as the protein level. SETDB1 promoter activity is increased to approximately 30-fold in normal condition, but the activity is significantly inhibited in the PTX treated group. In addition, p53 transfection inhibits SETDB1 promoter activity. The p53 protein directly binds to proximal region of the SETDB1 promoter, and H3K9me3 occupancy in this region also increased in the presence of p53. Immunoprecipitation experiment showed interaction of p53 and SUV39H1, suggesting that association of p53 and SUV39H1 is responsible for increased H3K9me3 occupancy and transcription repression of SETDB1. This result demonstrates that PTX down-regulates SETDB1 gene expression in a p53 dependent manner, and p53 might participate in heterochromatic repression on the promoter regions of SETDB1.