生物
癌症研究
BRD4
组蛋白脱乙酰基酶
组蛋白
表观遗传学
伏立诺他
胰腺癌
溴尿嘧啶
基因
癌症
遗传学
作者
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
摘要
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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