Journal
ONCOTARGET
Volume 8, Issue 12, Pages 19074-19088Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.13572
Keywords
histone deacetylase inhibitor; SAHA; AP-1; pancreatic cancer; cancer-associated fibroblasts
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Funding
- T32 Training Award from the National Institute of Health [NIH T32DK07180-39]
- Gerald S. Levey Surgical Research Award
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Although histone deacetylase inhibitors (HDACi) are a promising class of anticancer drugs, thus far, they have been unsuccessful in early phase clinical trials for pancreatic ductal adenocarcinoma (PDAC). One potential reason for their poor efficacy is the tumor stroma, where cancer-associated fibroblasts (CAFs) are a prominent cell type and a source of resistance to cancer therapies. Here, we demonstrate that stromal fibroblasts contribute to the poor efficacy of HDACi's in PDAC. HDACi-treated fibroblasts show increased biological aggressiveness and are characterized by increased secretion of pro-inflammatory tumor-supportive cytokines and chemokines. We find that HDAC2 binds to the enhancer and promoter regions of pro-inflammatory genes specifically in CAFs and in silico analysis identified AP-1 to be the most frequently associated transcription factor bound in these regions. Pharmacologic inhibition of pathways upstream of AP-1 suppresses the HDACi-induced inflammatory gene expression and tumor-supportive responses in fibroblasts. Our findings demonstrate that the combination of HDACi's with chemical inhibitors of the AP-1 signaling pathway attenuate the inflammatory phenotype of fibroblasts and may improve the efficacy of HDACi in PDAC and, potentially, in other solid tumors rich in stroma.
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