TY - JOUR
T1 - Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4-and MYC-dependent manner
AU - Mishra, Vivek Kumar
AU - Wegwitz, Florian
AU - Kosinsky, Robyn Laura
AU - Sen, Madhobi
AU - Baumgartner, Roland
AU - Wulff, Tanja
AU - Siveke, Jens T.
AU - Schildhaus, Hans Ulrich
AU - Najafova, Zeynab
AU - Kari, Vijayalakshmi
AU - Kohlhof, Hella
AU - Hessmann, Elisabeth
AU - Johnsen, Steven A.
N1 - Publisher Copyright:
© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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.
AB - 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.
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U2 - 10.1093/nar/gkx212
DO - 10.1093/nar/gkx212
M3 - Article
C2 - 28369619
AN - SCOPUS:85027026620
SN - 0305-1048
VL - 45
SP - 6334
EP - 6349
JO - Nucleic acids research
JF - Nucleic acids research
IS - 11
ER -