P300 inhibition enhances gemcitabine-induced apoptosis of pancreatic cancer

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.

Disruption of Broad Epigenetic Domains in PDAC Cells by HAT Inhibitors

“…We have previously shown that the two HAT inhibitors, ICG-001 and C646, differentially impair the global gene expression levels in human pancreatic and colorectal cancer cell lines [37]. Additionally, other work has shown that ICG-001 and C646 reduce tumorigenicity of pancreatic cancer cell models [38][39][40] and ICG-001 has been used in clinical trials for pancreatic cancer (NCT01302405). However, the impact of HAT inhibitor treatment on histone acetylation remains unknown.…”

Leptin signaling and cancer chemoresistance: Perspectives

“…Furthermore, the expression of leptin in gastro-esophageal adenocarcinomas was associated with chemoresistance. The use of leptin receptor antagonist SHLA increased the sensitivity to Cisplatin in the resistant gastric cancer cell line, AGS Cis5, and the oesophageal adenocarcinoma cell line, OE33[134]. …”

Prognostic role of upregulated P300 expression in human cancers: A clinical study of synovial sarcoma and a meta‑analysis

“…However, P300 overexpression was not significantly associated with OS. Although P300 has been observed as a tumour suppressor in the majority of studies, its oncogenic role has also been confirmed in multiple cancer types, where it is involved in the EMT (23,27,28), proliferation (29,30) and apoptosis (30,31). Gao et al (16) suggested that high expression of P300 enhanced EMT of HCC cells, and Liao et al (27) also indicates that P300 promotes EMT in an NPC cell line.…”

“…Inagaki et al (29), indicated that core-binding protein/P300 histone acetyltransferase activity is responsible for epigenetic regulation of proliferation and invasion in HCC cells, and Dou et al (32) suggested that midazolam inhibits the proliferation of human head and neck SCC cells by downregulating P300 expression. Gao et al (30) reported that the P300 inhibitor C646 induces cell cycle arrest and apoptosis in acute myeloid leukemia cells and Ono et al (31) indicated that P300 inhibition enhances the gemcitabine-induced apoptosis of pancreatic cancer cells. Table IV.…”