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


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
CSHL Authors:
Communities: CSHL labs > Koo Lab
CSHL labs > Preall lab
CSHL labs > Vakoc lab
Depositing User: Matthew Dunn
Date: 26 May 2020
Date Deposited: 14 Dec 2020 20:42
Last Modified: 14 Dec 2020 20:42
PMCID: PMC7261015
Related URLs:
URI: https://repository.cshl.edu/id/eprint/39630

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