title: CLCA2, a target of the p53 family, negatively regulates cancer cell migration and invasion.
abstract: The tumor suppressor p53 transcriptionally regulates a number of genes that are involved in cell-cycle inhibition, apoptosis and the maintenance of genetic stability. Recent studies suggest that p53 also contributes to the regulation of cell migration and invasion. Here, we show that human chloride channel accessory-2 (CLCA2) is a target gene of the p53 family (p53, p73 and p63). CLCA2 is induced by DNA damage in a p53-dependent manner. The p53 family proteins activate the CLCA2 promoter by binding directly to the conserved consensus p53-binding site present in the CLCA2 promoter. In terms of function, ectopic expression of CLCA2 inhibited cancer cell migration. In contrast, silencing CLCA2 with siRNA stimulated cancer cell migration and invasion. We also found that inactivation of CLCA2 enhanced the expression of focal adhesion kinase (FAK), as well as its promoter activation. A small-molecule FAK inhibitor reduced the effect of CLCA2 siRNA on cell migration and invasion, suggesting that CLCA2 inhibits cancer cell migration and invasion through suppression of the FAK signaling pathway. Furthermore, there was an inverse correlation between CLCA2 and FAK expression in 251 human breast cancer tissues. These results strongly suggest that CLCA2 is involved in the p53 tumor suppressor network and has a significant effect on cell migration and invasion.
authors.affiliation: Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Ryota
authors.initials: R
authors.lastname: Koyama
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.forename: Takehiro
authors.initials: T
authors.lastname: Hirano
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tamura
authors.forename: Jun
authors.initials: J
authors.lastname: Sugisaka
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Masashi
authors.initials: M
authors.lastname: Idogawa
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokino
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics*; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C120066:CLCA2 protein, human; D018118:Chloride Channels; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D051416:Focal Adhesion Protein-Tyrosine Kinases