ZBED2 is an antagonist of interferon regulatory factor 1 and modifies cell identity in pancreatic cancer

Somerville, T. D. D., Xu, Y., Wu, X. S., Maia-Silva, D., Hur, S. K., de Almeida, L. M. N., Preall, J. B., Koo, P. K., Vakoc, C. R. (May 2020) ZBED2 is an antagonist of interferon regulatory factor 1 and modifies cell identity in pancreatic cancer. Proc Natl Acad Sci U S A, 117 (21). pp. 11471-11482. ISSN 0027-8424 (Print)0027-8424

Abstract

Lineage plasticity is a prominent feature of pancreatic ductal adenocarcinoma (PDA) cells, which can occur via deregulation of lineage-specifying transcription factors. Here, we show that the zinc finger protein ZBED2 is aberrantly expressed in PDA and alters tumor cell identity in this disease. Unexpectedly, our epigenomic experiments reveal that ZBED2 is a sequence-specific transcriptional repressor of IFN-stimulated genes, which occurs through antagonism of IFN regulatory factor 1 (IRF1)-mediated transcriptional activation at cooccupied promoter elements. Consequently, ZBED2 attenuates the transcriptional output and growth arrest phenotypes downstream of IFN signaling in multiple PDA cell line models. We also found that ZBED2 is preferentially expressed in the squamous molecular subtype of human PDA, in association with inferior patient survival outcomes. Consistent with this observation, we show that ZBED2 can repress the pancreatic progenitor transcriptional program, enhance motility, and promote invasion in PDA cells. Collectively, our findings suggest that high ZBED2 expression is acquired during PDA progression to suppress the IFN response pathway and to promote lineage plasticity in this disease.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification 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 organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell proliferation 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 bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types > pancreatic cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:	Vakoc, Christopher R. Koo, Peter K Preall, Jonathan Somerville, Timothy Xu, Yali Wu, Xiaoli Maia-Silva, Diogo Hur, Stella K. de Almeida, Larissa M N
Communities:	CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL labs > Koo Lab CSHL labs > Preall lab CSHL labs > Vakoc lab School of Biological Sciences > Publications
Depositing User:	Matthew Dunn
Date:	26 May 2020
Date Deposited:	14 Dec 2020 20:42
Last Modified:	01 Feb 2024 18:44
PMCID:	PMC7261015
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/39630

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