Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumour that is characteristically unresponsive to most chemotherapeutic regimens. Bromodomain and extra terminal domain (BET) inhibitors that specifically repress the function of BET family proteins, such as BRD4, are under evaluation in clinical trials for their activity in repressing cancer growth. However, resistance to BET inhibitors has hindered their further clinical application in pancreatic cancer. We previously reported that FBP1 contributes to the resistance to BET inhibitors, but the underlying mechanism of this resistance remains unclear. Herein, we demonstrate that FBP1 is a binding partner of BRD4 in pancreatic cancer cells. We reveal that FBP1 binds to the BD2 domain of BD4 in an acetylation-dependent manner. Moreover, we found that Tip60 and HDAC3 were key to the acetylation and de-acetylation of FBP1 at K110 and K113, which are critical for mediating FBP1-BRD4 binding in pancreatic cancer cells. Furthermore, our data indicate that FBP1 decreases the expression of genes downstream of BRD4 to inhibit pancreatic cancer cell progression. Our results, therefore, provide evidence of the novel anti-tumour effect of FBP1 via its blockade of BRD4 function in pancreatic cancer cells.