Differential role of BET family proteins in regulating collagen I in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a uniformly lethal malignancy. PDAC is associated with dense collagen-rich stroma, which not only provides barrier to drug delivery but it can also mediate oncogenic signals in the cancer cells. This collagen rich-stroma, which can account for up to 90% of the tumor mass, consists of fibroblasts and pancreatic stellate cells (PSCs) that deposit collagen. In recent years there has been increasing interest in targeting the bromodomain and extraterminal (BET) family of proteins in a number of cancer types with small-molecule BET inhibitors. BET proteins BRD2, BRD3, BRD4 and testis-specific BRDT play a major role in epigenetic regulation of gene transcription. We have previously shown that treatment with BET inhibitors and transfection with BRD4 siRNA decrease growth of PDAC cells. Here we show that BET proteins are expressed in primary PSCs and play a differential role in in the regulation of collagen I. BRD2 and BRD3 function as transcriptional co-repressors while BRD4 function as of co-activator of collagen I. Collectively, our data demonstrate for the first time that BET family proteins BRD2, BRD3, and BRD4 play a differentiate role in the regulation of collagen I in PDAC.