P300 inhibition enhances gemcitabine-induced apoptosis of pancreatic cancer.
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.
Department of Surgery, Michigan State University, College of Human Medicine, Lansing, MI, USA.
Hiroaki
H
Ono
Departments of Surgery, Basic Science and Pathology, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND, USA.
Marc D
MD
Basson
Department of Surgery, Michigan State University, College of Human Medicine, Lansing, MI, USA.
Hiromichi
H
Ito
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D000093542:Gemcitabine
D034741:RNA, Small Interfering; D003841:Deoxycytidine; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D000093542:Gemcitabine
DNA damage repair; gemcitabine; histone acetyl transferase; p300; pancreatic cancer