Abstract 4500: BET proteins regulate hyaluronan synthases in pancreatic ductal adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with an extensive desmoplasia which is composed of multiple extracellular matrix components, including collagen, fibronectin, laminin, and hyaluronan (HA). Inhibitors targeting bromodomain and extra-terminal (BETi) proteins have emerged as potential therapeutic agents and are in clinical trials for a range of malignancies. We have previously shown that BETi attenuate fibrosis in vivo by decreasing collagen expression; however, the effect of BETi on HA has not been previously evaluated. Increased HA, which is synthesized by HA synthases (HAS), is associated with poor outcome in PDAC. Targeting HA has been postulated to provide a potential therapeutic opportunity to overcome PDAC chemo-resistance. Preclinical data have demonstrated that enzymatic degradation of HA with PEGPH20 remodels the tumor microenvironment, decreases the interstitial pressure and enhance the drug entry in tumors. Several ongoing clinical trials are evaluating PEGPH20 in combination with chemotherapies. We now report that BET inhibitors markedly decrease expression of HAS2 and HAS3, which are overexpressed in PDAC.

Purpose: The aim of this study is to investigate the role of BET proteins in HA synthesis.

Methods: mRNA expression levels HAS2 and HAS3 were determined in a panel of 7 PDAC cell lines by quantitative real-time RT-PCR. Protein expression was determined by western blotting.

Results: We found that treatment with BET inhibitors decrease the expression of HAS2 and HAS3 in all cell lines. Furthermore, siRNA mediated knockdown of individual BET proteins demonstrated that HAS2 is primarily regulated by BRD2, while HAS3 is primarily regulated by BRD4.

Conclusion: Our results demonstrate that BET proteins play a role in HA synthesis by regulating expression of HAS2 and HAS3 enzymes.

Citation Format: Krishan Kumar, Kazumi Ebine, Thao Pham, Meng Shang, Hidayatullah G. Munshi. BET proteins regulate hyaluronan synthases in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4500.