C12orf48, termed PARP-1 binding protein, enhances poly(ADP-ribose) polymerase-1 (PARP-1) activity and protects pancreatic cancer cells from DNA damage

• Published in: Genes chromosomes & cancer 2011-01, Vol.50 (1), p.13-24
• Main Authors: Piao, Lianhua, Nakagawa, Hidewaki, Ueda, Koji, Chung, Suyoun, Kashiwaya, Kotoe, Eguchi, Hidetoshi, Ohigashi, Hiroaki, Ishikawa, Osamu, Daigo, Yataro, Matsuda, Koichi, Nakamura, Yusuke
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; ADP-ribosylation; Blotting, Northern; Blotting, Western; Carcinoma, Pancreatic Ductal - enzymology; Carcinoma, Pancreatic Ductal - genetics; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Cycle; Cell Extracts; Cell Line, Tumor; DNA Damage; DNA microarrays; DNA-Binding Proteins; Enzymatic activity; Gene expression; Gene Expression Profiling; Gene Knockdown Techniques; Histocytochemistry; Humans; Malignancy; Oligonucleotide Array Sequence Analysis; Pancreatic cancer; Pancreatic Neoplasms - enzymology; Pancreatic Neoplasms - genetics; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; Protein Binding; Protein Interaction Mapping; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; siRNA
• ISSN: 1045-2257; 1098-2264; 1098-2264
• DOI: 10.1002/gcc.20828

To identify novel therapeutic targets for aggressive and therapy‐resistant pancreatic cancer, we had previously performed expression profile analysis of pancreatic cancers using microarrays and found dozens of genes trans‐activated in pancreatic ductal adenocarcinoma (PDAC) cells. Among them, this study focused on the characterization of a novel gene C12orf48 whose overexpression in PDAC cells was validated by Northern blot and immunohistochemical analysis. Its overexpression was observed in other aggressive and therapy‐resistant malignancies as well. Knockdown of C12orf48 by siRNA in PDAC cells significantly suppressed their growth. Importantly, we demonstrated that C12orf48 protein could directly interact with Poly(ADP‐ribose) Polymerase‐1 (PARP‐1), one of the essential proteins in the repair of DNA damage, and positively regulate the poly(ADP‐ribosyl)ation activity of PARP‐1. Depletion of C12orf48 sensitized PDAC cells to agents causing DNA damage and also enhanced DNA damage‐induced G2/M arrest through reduction of PARP‐1 enzymatic activities. Hence, our findings implicate C12orf48, termed PARP‐1 binding protein (PARPBP), or its interaction with PARP‐1 to be a potential molecular target for development of selective therapy for pancreatic cancer. © 2010 Wiley‐Liss, Inc.