10370

CITED2

ASD8|MRG-1|MRG1|P35SRJ|VSD2;Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2;CITED2;Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2

MSG-related protein 1|MSG1-related gene 1|cbp/p300-interacting transactivator 2|melanocyte-specific gene 1-related gene 1

6q23.3

protein-coding

BACKGROUND: Previous reports from these authors found that activation of peroxisome proliferator-activated receptor gamma (PPARgamma) suppressed hepatocellular carcinoma (HCC). This study sought to identify the molecular target of PPARgamma and characterize its antitumor effect in HCC. METHODS: Optimal PPARgamma binding activity was obtained using the PPARgamma agonist rosiglitazone (100 muM) as determined by enzyme-linked immunosorbent assay. Under PPARgamma activation, 114 PPARgamma downstream targets associated with cancer development were identified by oligonucleotide microarray and gene Ontology analysis. Among them, Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2 (CITED2) was the most prominent PPARgamma-bound target, as determined by chromatin immunoprecipitation-polymerase chain reaction. RESULTS: CITED2 messenger RNA and protein was significantly down-regulated in primary HCCs compared with their adjacent nontumor tissues. PPARgamma induced expression of CITED2 in HCC cell lines after adenovirus-PPARgamma transduction. The biological function of CITED2 was evaluated by loss- and gain-of-function assays. CITED2 knockdown in the hepatocyte cell line LO2 and HCC cell line Hep3B significantly increased cell viability and clonogenicity, and promoted G1 -S phase transition in both cell lines. In contrast, ectopic expression of CITED2 in HepG2 and BEL7404 HCC cell lines significantly suppressed cell growth. The tumor suppressive effect of CITED2 was associated with up-regulation of cyclin-dependent kinase inhibitors p15(INK4B) , p21(Wat1/Cip1) , p27(Kip1) , antiproliferative regulator interferon alpha 1, proapoptotic mediators including tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), TNFRSF25, caspase-8, granzyme A, and the tumor suppressor gene maspin. CITED2 was also associated with the down-regulation of cell cycle regulator cyclin D1, oncogene telomerase reverse transcriptase, and proinvasion/metastasis gene matrix metallopeptidase 2. CONCLUSIONS: CITED2 is a direct effector of PPARgamma for tumor suppression. cancer 2013. (c) 2012 American cancer Society.