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.
journal_name
Proc Natl Acad Sci U S Aauthors
Somerville TDD,Xu Y,Wu XS,Maia-Silva D,Hur SK,de Almeida LMN,Preall JB,Koo PK,Vakoc CRdoi
10.1073/pnas.1921484117subject
Has Abstractpub_date
2020-05-26 00:00:00pages
11471-11482issue
21eissn
0027-8424issn
1091-6490pii
1921484117journal_volume
117pub_type
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