Regulation of Chromatin Remodeling and Transcription Involved in Tumor suppression and its Dysregulation in Oral Cancer

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Previously, we have reported that DRIL1, an ARID (AX-rich interaction domain) DNA-binding protein, is regulated by p53 tumor suppressor. In this study, we investigated functional roles of DRIL1 in the p53 regulatory pathway, and dysregulation of its pathway in oral cancer. Here we show that DRIL1 specifically binds to the promoter of p21Waf1/Cip1, a p53-target gene important for cell cycle arrest Mutation of the DRIL1 binding sites diminished transactivation of the p21 promoter following p53 overexpression and DNA damage. Consistently, DRIL1 overexpression induces p21 transcription and co-expression of DRIL1 with p53 synergistically activates the p21 promoter. Furthermore, We also identified in vivo binding sites of DRIL1 in pro-apoptotic p53-target genes. Co-expression of DRIL1 and p53 synergistically induces pro-apoptotic gene expression and facilitated p53-mediated apoptosis. Silencing DRIL1 expression by DRILL shRNA down-regulated transcription of p53-target genes and apoptosis ind … More uced by DNA damage, indicating that DRIL1 play an important role in p53-target gene expression and apoptosis. Moreover, DRIL1 directly binds to p53 and PML, a component of PML nuclear bodies (NBs), in which many proteins involved in post translational modifications of p53 are co localized Consistently, we have found that silencing DRIL1 expression by siRNA surely impaired acetylation and phosphorylation of p53, suggesting that DRIL1 plays a role in the post-translational modifications of p53 protein. In a separate study, we found that the defect in phosphorylation of p53 on Ser46 accounts for the acquisition of the p53 resistance in HSC-3 oral cancer cells. Furthermore, coinfection of adenoviruses expressing DRIL1 and p53 efficiently induced apoptosis in p53-resistant HSC-3 cells accompanied by induction of pro-apoptotic p53-target genes. Collectively, these results demonstrate that DRIL1 is a p53-regulated transcription factor that cooperates with p53 to strengthen p53 dependent transcription and trigger apoptosis through its direct binding to p53-target genes, suggesting a positive autoregulatory mechanism of the p53 pathway. Less