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Nucleic Acids Res. 2017 Jun 20;45(11):6334-6349. doi: 10.1093/nar/gkx212.

Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4- and MYC-dependent manner.

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Department of General, Visceral and Pediatric Surgery, Göttingen Center for Molecular Biosciences, University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.
4SC AG, Am Klopferspitz 19a, 82152 Planegg-Martinsried, Germany.
German Consortium for Translational Cancer Research (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
Department of Pathology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.
Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.


Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a particularly dismal prognosis. Histone deacetylases (HDAC) are epigenetic modulators whose activity is frequently deregulated in various cancers including PDAC. In particular, class-I HDACs (HDAC 1, 2, 3 and 8) have been shown to play an important role in PDAC. In this study, we investigated the effects of the class I-specific HDAC inhibitor (HDACi) 4SC-202 in multiple PDAC cell lines in promoting tumor cell differentiation. We show that 4SC-202 negatively affects TGFβ signaling and inhibits TGFβ-induced epithelial-to-mesenchymal transition (EMT). Moreover, 4SC-202 markedly induced p21 (CDKN1A) expression and significantly attenuated cell proliferation. Mechanistically, genome-wide studies revealed that 4SC-202-induced genes were enriched for Bromodomain-containing Protein-4 (BRD4) and MYC occupancy. BRD4, a well-characterized acetyllysine reader, has been shown to play a major role in regulating transcription of selected subsets of genes. Importantly, BRD4 and MYC are essential for the expression of a subgroup of genes induced by class-I HDACi. Taken together, our study uncovers a previously unknown role of BRD4 and MYC in eliciting the HDACi-mediated induction of a subset of genes and provides molecular insight into the mechanisms of HDACi action in PDAC.

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