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

Vivek Kumar Mishra, Florian Wegwitz, Robyn Laura Kosinsky, Madhobi Sen, Roland Baumgartner, Tanja Wulff, Jens T. Siveke, Hans Ulrich Schildhaus, Zeynab Najafova, Vijayalakshmi Kari, Hella Kohlhof, Elisabeth Hessmann, Steven A. Johnsen

Research output: Contribution to journalArticle

27 Scopus citations

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' signaling and inhibits TGF'-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 Bromodomaincontaining 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 HDACimediated induction of a subset of genes and provides molecular insight into the mechanisms of HDACi action in PDAC.

Original languageEnglish (US)
Pages (from-to)6334-6349
Number of pages16
JournalNucleic acids research
Volume45
Issue number11
DOIs
StatePublished - Jun 1 2017

ASJC Scopus subject areas

  • Genetics

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    Mishra, V. K., Wegwitz, F., Kosinsky, R. L., Sen, M., Baumgartner, R., Wulff, T., Siveke, J. T., Schildhaus, H. U., Najafova, Z., Kari, V., Kohlhof, H., Hessmann, E., & Johnsen, S. A. (2017). Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4-and MYC-dependent manner. Nucleic acids research, 45(11), 6334-6349. https://doi.org/10.1093/nar/gkx212