Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4-and MYC-dependent manner
2017 | journal article. A publication with affiliation to the University of Göttingen.
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Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4-and MYC-dependent manner
Mishra, V. K.; Wegwitz, F.; Kosinsky, R. L.; Sen, M. ; Baumgartner, R.; Wulff, T. & Siveke, J. T. et al. (2017)
Nucleic Acids Research, 45(11) pp. 6334-6349. DOI: https://doi.org/10.1093/nar/gkx212
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Details
- Authors
- Mishra, Vivek Kumar; Wegwitz, Florian; Kosinsky, Robyn Laura; Sen, Madhobi ; Baumgartner, Roland; Wulff, Tanja; Siveke, Jens T.; Schildhaus, Hans-Ulrich; Najafova, Zeynab; Kari, Vijayalakshmi; Kohlhof, Hella; Hessmann, Elisabeth ; Johnsen, Steven A.
- Abstract
- 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 Ispecific HDAC inhibitor (HDACi) 4SC-202 in multiple PDAC cell lines in promoting tumor cell differentiation. We show that 4SC-202 negatively affects TGF beta signaling and inhibits TGF beta-induced epithelial-tomesenchymal 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.
- Issue Date
- 2017
- Status
- published
- Publisher
- Oxford Univ Press
- Journal
- Nucleic Acids Research
- ISSN
- 1362-4962; 0305-1048
- Sponsor
- Open-Access-Publikationsfonds 2017