Epigenetic silencing of CYP24 in the tumor microenvironment

J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):338-42. doi: 10.1016/j.jsbmb.2010.03.046. Epub 2010 Mar 19.


Calcitriol (1,25 dihydroxycholecalciferol) has significant anti-tumor activity in vitro and in vivo in a number of tumor model systems. We developed a system for isolation of fresh endothelial cells from tumors and Matrigel environments which demonstrate that CYP24, the catabolic enzyme involved in vitamin D signaling, is epigenetically silenced selectively in tumor-derived endothelial cells (TDEC). TDEC maintain phenotypic characteristics which are distinct from endothelial cells isolated from normal tissues and from Matrigel plugs (MDEC). In TDEC, calcitriol induces G(0)/G(1) arrest, modulates p27 and p21, and induces apoptotic cell death and decreases P-Erk and P-Akt. In contrast, endothelial cells isolated from normal tissues and MDEC are unresponsive to calcitriol-mediated anti-proliferative effects despite intact signaling through the vitamin D receptor (VDR). In TDEC, which are sensitive to calcitriol, the CYP24 promoter is hypermethylated in two CpG island regions located at the 5'end; this hypermethylation may contribute to gene silencing of CYP24. The extent of methylation in these two regions is significantly less in MDEC. Lastly, treatment of TDEC with a DNA methyltransferase inhibitor restores calcitriol-mediated induction of CYP24 and resistance to calcitriol. These data suggest that epigenetic silencing of CYP24 modulates cellular responses to calcitriol.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Blood Platelets
  • Calcitriol / metabolism
  • Cell Cycle
  • Collagen / chemistry
  • Collagen / metabolism
  • CpG Islands
  • Drug Combinations
  • Endothelial Cells / cytology
  • Epigenesis, Genetic*
  • Humans
  • Laminin / chemistry
  • Laminin / metabolism
  • Neoplasms / genetics*
  • Oligonucleotide Array Sequence Analysis / methods
  • Phenotype
  • Platelet Adhesiveness
  • Proteoglycans / chemistry
  • Proteoglycans / metabolism
  • Receptors, Calcitriol / metabolism
  • Signal Transduction
  • Steroid Hydroxylases / genetics*
  • Vitamin D3 24-Hydroxylase


  • Drug Combinations
  • Laminin
  • Proteoglycans
  • Receptors, Calcitriol
  • matrigel
  • Collagen
  • Steroid Hydroxylases
  • Vitamin D3 24-Hydroxylase
  • Calcitriol