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

URL: https://pubmed.ncbi.nlm.nih.gov/32385160/
DOI: 10.1073/pnas.1921484117

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:
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:
URI: https://repository.cshl.edu/id/eprint/39630

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