PDLIM2 Expression Is Driven by Vitamin D and Is Involved in the Pro-Adhesion, and Anti-Migration and -Invasion Activity of Vitamin D

Oncogene. 2014 Apr 10;33(15):1904-11. doi: 10.1038/onc.2013.123. Epub 2013 Apr 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Cell Adhesion / drug effects
  • Cell Adhesion / genetics
  • Cell Movement* / drug effects
  • Cell Movement* / genetics
  • Chromatin Immunoprecipitation
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • LIM Domain Proteins / biosynthesis*
  • LIM Domain Proteins / genetics
  • MCF-7 Cells
  • Microfilament Proteins / biosynthesis*
  • Microfilament Proteins / genetics
  • Neoplasm Invasiveness / genetics
  • Promoter Regions, Genetic / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / metabolism
  • Transcriptional Activation / drug effects
  • Vitamin D / analogs & derivatives*
  • Vitamin D / pharmacology

Substances

  • Antineoplastic Agents
  • LIM Domain Proteins
  • Microfilament Proteins
  • PDLIM2 protein, human
  • Receptors, Calcitriol
  • dihydroxy-vitamin D3
  • Vitamin D