Journal
ONCOTARGET
Volume 7, Issue 38, Pages 61469-61484Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.11129
Keywords
pancreatic ductal adenocarcinoma (PDAC); cancer -associated fibroblast (CAF); epigenetics; bromodomain and extraterminaf domain (BET) proteins; JO1
Categories
Funding
- KAKENHI [15K09040, 16K09390, 24591009]
- Takeda Science Foundation
- Uehara Memorial Foundation
- Grants-in-Aid for Scientific Research [15K09040, 24591009, 16K09390] Funding Source: KAKEN
Ask authors/readers for more resources
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-beta pathways as potent regulators of CAF activation and suppressed the expression of alpha-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-beta-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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available