title: Protein-arginine deiminase 2 suppresses proliferation of colon cancer cells through protein citrullination.
abstract: Expression of the gene for protein-arginine deiminase 2 (PADI2) has been shown to be downregulated in colon cancer, with such downregulation being indicative of a poor prognosis in individuals with this disease. We have now examined the expression of PADI2 in matched colon cancer and normal colon tissue specimens as well as in colon cancer cell lines. We found that isoform 1 of PADI2 is the predominant isoform in colon tissue and is downregulated during colon carcinogenesis. Immunohistochemical analysis showed that PADI2 is expressed in normal colonic epithelial cells. Overexpression of PADI2 isoform 1 suppressed the proliferation of colon cancer cells in vitro in association with increased protein citrullination. Expression of a catalytically inactive mutant (C647A) of PADI2 or of PADI2 isoform 2 did not induce such effects, indicating that the protein citrullination activity of PADI2 is required for inhibition of cell growth. The growth defect induced by PADI2 was not attributable to increased apoptosis but rather was accompanied by arrest of cell cycle progression in G1phase. Finally, we detected citrullinated proteins in normal colon tissue by immunoblot analysis. Our data thus suggest that PADI2 suppresses the proliferation of colonic epithelial cells through catalysis of protein citrullination, and that downregulation of PADI2 expression might therefore contribute to colon carcinogenesis.
authors.affiliation: Department of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, ART, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Funayama
authors.affiliation: Department of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, ART, Graduate School of Medicine, Tohoku University, Sendai, Japan.|Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Mizuma
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Fujishima
authors.affiliation: Department of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, ART, Graduate School of Medicine, Tohoku University, Sendai, Japan.|Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Ohnuma
authors.affiliation: Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Unno
authors.affiliation: Department of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, ART, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
mesh_terms: D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D002956:Citrulline / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D006867:Hydrolases / Q000235:genetics* / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007527:Isoenzymes; D002956:Citrulline; D006867:Hydrolases; C000620352:PADI2 protein, human; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases
keywords: Cell proliferation; PADI2; colorectal cancer; epigenomic regulation; protein citrullination