Interplay between interferon regulatory factor 1 and BRD4 in the regulation of PD-L1 in pancreatic stellate cells

Ebine, K., Kumar, K., Pham, T. N., Shields, M. A., Collier, K. A., Shang, M., DeCant, B. T., Urrutia, R., Hwang, R. F., Grimaldo, S., Principe, D. R., Grippo, P. J., Bentrem, D. J., Munshi, H. G. (September 2018) Interplay between interferon regulatory factor 1 and BRD4 in the regulation of PD-L1 in pancreatic stellate cells. Sci Rep, 8 (1). p. 13225. ISSN 2045-2322

Abstract

The fibrotic reaction is a characteristic feature of human pancreatic ductal adenocarcinoma (PDAC) tumors. It is associated with activation and proliferation of pancreatic stellate cells (PSCs), which are key regulators of fibrosis in vivo. While there is increasing interest in the regulation of PD-L1 expression in cancer and immune cells, the expression and regulation of PD-L1 in other stromal cells, such as PSCs, has not been fully evaluated. Here we show that PSCs in vitro express higher PD-L1 mRNA and protein levels compared to the levels present in PDAC cells. We show that inhibitors targeting bromodomain and extra-terminal (BET) proteins and BRD4 knockdown decrease interferon-gamma (IFN-gamma)-induced PD-L1 expression in PSCs. We also show that c-MYC, one of the well-established targets of BET inhibitors, does not mediate IFN-gamma-regulated PD-L1 expression in PSCs. Instead we show that interferon regulatory factor 1 (IRF1) mediates IFN-gamma-induced PD-L1 expression in PSCs. Finally, while we show that BET inhibitors do not regulate IFN-gamma-induced IRF1 expression in PSCs, BET inhibitors decrease binding of IRF1 and BRD4 to the PD-L1 promoter. Together, these results demonstrate the interplay between IRF1 and BRD4 in the regulation of PD-L1 in PSCs.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > neoplasms bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > BET bromodomain coactivator protein bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > BET bromodomain coactivator protein > Brd4 organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types > pancreatic cancer organs, tissues, organelles, cell types and functions > cell types and functions > cell types > pancreatic stellate cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > pancreatic stellate cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > pancreatic stellate cells bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor diseases & disorders > cancer > cancer types
CSHL Authors:	Shields, Mario
Communities:	CSHL labs > Egeblad lab
Depositing User:	Matthew Dunn
Date:	5 September 2018
Date Deposited:	13 Sep 2018 19:06
Last Modified:	20 Feb 2024 18:44
PMCID:	PMC6125340
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/37197

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