title: PDLIM2 expression is driven by vitamin D and is involved in the pro-adhesion, and anti-migration and -invasion activity of vitamin D.
abstract: 1Alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3], the biologically active form of vitamin D3, is a pleiotropic hormone that exerts its effects on a wide range of tissues, resulting in different biological responses such as anticancer activity. It is the ligand of the vitamin D receptor (VDR), a nuclear receptor with transactivating capacity. We demonstrated in this study that 1,25(OH)2D3 induces PDZ-LIM domain-containing protein 2 (PDLIM2) expression. PDLIM2 is an adaptor molecule that links different components of the cytoskeleton, and was recently shown to be repressed in human breast cancer cells by hypermethylation of regulatory promoter regions, leading to enhanced tumorigenicity. We demonstrated that PDLIM2 was a direct target gene of 1,25(OH)2D3; its upregulation was VDR-dependent and a functional VDRE in the promoter was identified. Moreover, 1,25(OH)2D3 induced demethylation of the PDLIM2 promoter, leading to enhanced transcription. Finally, PDLIM2 was found to be crucial for 1,25(OH)2D3-induced cell adhesion and for mediating the ability of 1,25(OH)2D3 to suppress cancer cell migration and invasion. This study provides mechanistic insights into the anticancer activities of 1,25(OH)2D3 in human breast cancer cells.
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Vanoirbeek
authors.affiliation: 1] Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium [2] Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/KU Leuven, Leuven, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Eelen
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Verlinden
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Carmeliet
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Mathieu
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Bouillon
authors.affiliation: Department of Biochemistry, University College, Cork, Ireland.
authors.forename: R
authors.initials: R
authors.lastname: O'Connor
authors.affiliation: Hillman Cancer Center Research Pavilion, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Verstuyf
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D060588:LIM Domain Proteins / Q000096:biosynthesis* / Q000235:genetics; D061986:MCF-7 Cells; D008840:Microfilament Proteins / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; C502929:PDLIM2 protein, human; D018167:Receptors, Calcitriol; C118756:dihydroxy-vitamin D3; D014807:Vitamin D