Bromodomain-containing
protein 7 (BRD7) was found to be down-expressed in
nasopharyngeal carcinoma as well as
breast cancer and to function as a potential
tumor suppressor. BRD7 interacts with p53 and is required for p53-dependent oncogene-induced senescence. However, the mechanism how BRD7 functions as
tumor suppressor roles in
breast cancer remains unclear. MTT, colony formation assay, cell cycle, cell apoptosis, and tumorigenicity assays were performed to evaluate the
biological functions of BRD7 in
breast cancer cells in vitro and in vivo. Real-time PCR, western blot,
luciferase reporter gene assays, and co-immunoprecipitation were used to examine the gene expression, transcription activation and
protein-
protein interaction. We reported that BRD7 effectively suppressed cell proliferation and
tumor growth in vitro and in vivo. In addition, BRD7 increased p53 protein stability through
ubiquitin-dependent
proteasome pathway and regulated the expression of p53 downstream target genes by activating its transcriptional activity in breast
cancers harboring wild-type p53. Mechanistically, BRD7 decreased phosphorylation and activation of MDM2 via inactivating its upstream
kinase AKT depending on the bromodomain of BRD7, therefore BRD7 significantly reduced the amounts of phosphorylated MDM2 binding with p53 eventually decreasing ubiquitination level of p53. Furthermore, silencing the expression of p53 at least partly reversed the inhibition effect of BRD7 on cell proliferation and
tumor growth in vitro and in vivo. Our studies identify that BRD7 stabilizes p53 by inhibiting the phosphorylation of MDM2 via AKT pathway dependent on its bromodomain to function as a
tumor suppressor in
breast cancer harboring wild-type p53.