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

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.

• Authors: Keisuke Yamamoto, Keisuke Tateishi, Yotaro Kudo, Mayumi Hoshikawa, Mariko Tanaka, Takuma Nakatsuka, Hiroaki Fujiwara, Koji Miyabayashi, Ryota Takahashi, Yasuo Tanaka, Hideaki Ijichi, Yousuke Nakai, Hiroyuki Isayama, Yasuyuki Morishita, Taku Aoki, Yoshihiro Sakamoto, Kiyoshi Hasegawa, Norihiro Kokudo, Masashi Fukayama, Kazuhiko Koike
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 38 Pg. 61469-61484 (Sep 20 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27528027 (Publication Type: Journal Article)

Chemical References

• (+)-JQ1 compound
• ACTA2 protein, human
• Actins
• Azepines
• Cytokines
• Hedgehog Proteins
• Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• Transforming Growth Factor beta
• Triazoles
• bromodomain and extra-terminal domain protein, human

Topics

• Actins (metabolism)
• Animals
• Azepines (pharmacology, therapeutic use)
• Cancer-Associated Fibroblasts (drug effects, metabolism)
• Carcinoma, Pancreatic Ductal (drug therapy, pathology, surgery)
• Cell Line, Tumor
• Cell Proliferation
• Chromatin Immunoprecipitation
• Cytokines (metabolism)
• Disease Progression
• Epigenesis, Genetic (drug effects)
• Hedgehog Proteins (metabolism)
• Humans
• Immunohistochemistry
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Pancreas (pathology)
• Pancreatic Neoplasms (drug therapy, pathology, surgery)
• Primary Cell Culture
• Proteins (antagonists & inhibitors, genetics)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Transcription, Genetic (drug effects)
• Transforming Growth Factor beta (genetics, metabolism)
• Triazoles (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays