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

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.

authors

Somerville TDD,Xu Y,Wu XS,Maia-Silva D,Hur SK,de Almeida LMN,Preall JB,Koo PK,Vakoc CR

doi

10.1073/pnas.1921484117

subject

Has Abstract

pub_date

2020-05-26 00:00:00

pages

11471-11482

issue

21

eissn

0027-8424

issn

1091-6490

pii

1921484117

journal_volume

117

pub_type

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