Abstract
Prostate cancer (PCa) is the most prevalent malignancy among men with a rising mortality rate. Androgen deprivation therapy (ADT) effectively treats PCa. However, patients inevitably progress to castration-resistant prostate cancer (CRPC). There are still no effect methods for treating CRPC. The underlying mechanisms driving CRPC remain unclear. Methyl-CpG binding domain protein 3 (MBD3), a key member of the methyl-CpG binding protein family, exhibits high expression in lots of cancers. Here, we tried to find the mechanism of MBD3 in causing CRPC. We collected RNA-sequence data of PCa patients from public databases and collected CRPC samples from Tongji Hospital. Then, the expression of MBD3 in PCa samples was detected. By overexpression or knockdown MBD3, the role of MBD3 in affecting PCa cells proliferation was detected in vivo and vitro. Using public databases data, PCR, western blot and ChIP-qPCR experiments, the mechanism of MBD3 leading to PCa was analyzed. This study revealed that MBD3 is upregulated in both PCa and CRPC samples from public databases and clinical samples. Elevated MBD3 expression promotes CRPC cell proliferation by epigenetically silencing the tumor suppressor gene phosphatase and tensin homolog (PTEN). Furthermore, MBD3 is transcriptionally regulated by bromodomain-containing protein 4 (BRD4), and MBD3 knockdown enhances the sensitivity of CRPC cells to BET inhibitors. These findings suggest that the BRD4-MBD3-PTEN axis is a new pathway in CRPC, with MBD3 representing a potential therapeutic target, particularly in combination with BET inhibitors.