Stromal remodeling by the BET bromodomain inhibitor JQ1 suppresses the progression of human pancreatic cancer.

Content Provider	Europe PMC
Author	Yamamoto, Keisuke Tateishi, Keisuke Kudo, Yotaro Hoshikawa, Mayumi Tanaka, Mariko Nakatsuka, Takuma Fujiwara, Hiroaki Miyabayashi, Koji Takahashi, Ryota Tanaka, Yasuo Ijichi, Hideaki Nakai, Yousuke Isayama, Hiroyuki Morishita, Yasuyuki Aoki, Taku Sakamoto, Yoshihiro Hasegawa, Kiyoshi Kokudo, Norihiro Fukayama, Masashi Koike, Kazuhiko
Copyright Year	2016
Abstract	Inhibitors of bromodomain and extraterminal domain (BET) proteins, a family of chromatin reader proteins, have therapeutic efficacy against various malignancies. However, the detailed mechanisms underlying the anti-tumor effects in distinct tumor types remain elusive. Here, we show a novel antitumor mechanism of BET inhibition in pancreatic ductal adenocarcinoma (PDAC). We found that JQ1, a BET inhibitor, decreased desmoplastic stroma, a hallmark of PDAC, and suppressed the growth of patient-derived tumor xenografts (PDX) of PDACs. In vivo antitumor effects of JQ1 were not always associated with the JQ1 sensitivity of respective PDAC cells, and were rather dependent on the suppression of tumor-promoting activity in cancer-associated fibroblasts (CAFs). JQ1 inhibited Hedgehog and TGF-β pathways as potent regulators of CAF activation and suppressed the expression of α-SMA, extracellular matrix, cytokines, and growth factors in human primary CAFs. Consistently, conditioned media (CM) from CAFs promoted the proliferation of PDAC cells along with the activation of ERK, AKT, and STAT3 pathways, though these effects were suppressed when CM from JQ1-treated CAFs was used. Mechanistically, chromatin immunoprecipitation experiments revealed that JQ1 reduced TGF-β–dependent gene expression by disrupting the recruitment of the transcriptional machinery containing BET proteins. Finally, combination therapy with gemcitabine plus JQ1 showed greater efficacy than gemcitabine monotherapy against PDAC in vivo. Thus, our results reveal BET proteins as the critical regulators of CAF-activation and also provide evidence that stromal remodeling by epigenetic modulators can be a novel therapeutic option for PDAC.
Journal	Oncotarget
Volume Number	7
PubMed Central reference number	PMC5308665
Issue Number	38
PubMed reference number	27528027
e-ISSN	19492553
DOI	10.18632/oncotarget.11129
Language	English
Publisher	Impact Journals LLC
Publisher Date	2016-09-01
Access Restriction	Open
Rights License	This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: © 2016 Yamamoto et al.
Subject Keyword	pancreatic ductal adenocarcinoma (PDAC) cancer-associated fibroblast (CAF) epigenetics bromodomain and extraterminal domain (BET) proteins JQ1
Content Type	Text
Resource Type	Article
Subject	Oncology