Abstract
The transcriptional cofactor p300 has histone acetyltransferase activity (HAT) and has been reported to participate in chromatin remodeling and DNA repair. We hypothesized that targeting p300 can enhance the cytotoxicity of gemcitabine, which induces pancreatic cancer cell apoptosis by damaging DNA. Expression of p300 was confirmed in pancreatic cancer cell lines and human pancreatic adenocarcinoma tissues by western blotting and immunohistochemistry. When pancreatic cancer cells were treated with gemcitabine, p300 was recruited to chromatin within 24 hours, indicating the role in response to DNA damage. When p300 was gene-silenced with siRNA, histone acetylation was substantially reduced and pancreatic cancer cells were sensitized to gemcitabine. The selective p300 HAT inhibitor C646 similarly decreased histone acetylation, increased gemcitabine-induced apoptosis and thus enhanced the cytotoxicity of gemcitabine on pancreatic cancer cells. These findings indicate that p300 contributes to chemo-resistance of pancreatic cancer against gemcitabine and suggest that p300 and its HAT activity may be a potential therapeutic target to improve outcomes in patients with pancreatic cancer.
Highlights
Overall cancer mortality has declined over the past 2 decades in the United States, the mortality of patients with pancreatic cancer has not improved. [1] The poor efficacy of current chemotherapy for pancreatic cancer is a critical factor in these poor outcomes
C646 was previously reported to inhibit H3 histone acetylation at within a range of 10 uM through 50 uM for other types of cancer cells. [13, 21, 22] histone acetyltransferase activity (HAT) inhibition by C646 increased the cytotoxic effect of gemcitabine at 96 hours for pancreatic cancer cell lines (Figure 5B) and increased gemcitabine-induced apoptosis was confirmed by western blotting for cleaved Caspase 3 and PARP (Figure 5C)
These findings suggest that p300 protects pancreatic cancer cells against gemcitabine-induced DNA damage, at least partially by HAT-dependent manner and targeting p300 HAT activity can enhance the therapeutic efficacy of gemcitabine against pancreatic cancer
Summary
Overall cancer mortality has declined over the past 2 decades in the United States, the mortality of patients with pancreatic cancer has not improved. [1] The poor efficacy of current chemotherapy for pancreatic cancer is a critical factor in these poor outcomes. [1] The poor efficacy of current chemotherapy for pancreatic cancer is a critical factor in these poor outcomes. A novel target to enhance current chemotherapy is clearly needed to improve the outcomes of patients with pancreatic cancer. We hypothesized that p300 is associated with resistance to DNA-damaging chemotherapy and that targeting p300 can enhance the cytotoxicity of such chemotherapeutic agents in pancreatic cancer. We evaluated the effect on gemcitabine-induced DNA damage and apoptosis in pancreatic cancer of gene silencing of p300 and of pharmacological inhibition of p300 by the small molecule inhibitor C646. Our findings identify p300 as a novel molecular target to improve the efficacy of current chemotherapeutic regimens for patients with pancreatic cancer and improve their long-term outcomes
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