Stromal remodeling by the BET bromodomain inhibitor JQ1 suppresses the progression of human pancreatic cancer
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Keisuke Yamamoto1, Keisuke Tateishi1, Yotaro Kudo1, Mayumi Hoshikawa2, Mariko Tanaka3, Takuma Nakatsuka1, Hiroaki Fujiwara1, Koji Miyabayashi1, Ryota Takahashi1, Yasuo Tanaka1, Hideaki Ijichi1, Yousuke Nakai1, Hiroyuki Isayama1, Yasuyuki Morishita3,4, Taku Aoki2,5, Yoshihiro Sakamoto2, Kiyoshi Hasegawa2, Norihiro Kokudo2, Masashi Fukayama3, Kazuhiko Koike1
1Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
2Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
3Department of Pathology and Diagnostic Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
4Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
5Second Department of Surgery, Dokkyo Medical University, Mibu, Tochigi 321-0293, Japan
Keisuke Tateishi, email: [email protected]
Keywords: pancreatic ductal adenocarcinoma (PDAC), cancer-associated fibroblast (CAF), epigenetics, bromodomain and extraterminal domain (BET) proteins, JQ1
Received: March 21, 2016 Accepted: July 27, 2016 Published: August 09, 2016
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.
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