| Autor: |
Mishra, Vivek Kumar, Wegwitz, Florian, Kosinsky, Robyn Laura, Sen, Madhobi, Baumgartner, Roland, Wulff, Tanja, Siveke, Jens, Schildhaus, Hans-Ulrich, Najafova, Zeynab, Kari, Vijayalakshmi, Kohlhof, Hella, Hessmann, Elisabeth, Johnsen, Steven A. |
| Jazyk: |
angličtina |
| Rok vydání: |
2017 |
| Předmět: |
|
| Popis: |
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. OA gold |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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