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Epigenetic silencing of CYP24 in tumor-derived endothelial cells contributes to selective growth inhibition by calcitriol

Calcitriol (1,25-dihydroxycholecalciferol), the most active form of vitamin D, has selective anti-proliferative effects on tumor-derived endothelial cells (TDEC) compared with Matrigel-derived endothelial cells (MDEC). Although both cell types have an intact vitamin D receptor-signaling axis, this s...

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Main Authors: Chung, I., Karpf, A.R., Muindi, J.R., Conroy, J.M., Nowak, N.J., Johnson, C.S., Trump, D.L.
Format: Article
Language:English
Published: 2007
Subjects:
R Medicine
Online Access:http://eprints.um.edu.my/5079/1/Chung-2007-Epigenetic_silencing.pdf
http://eprints.um.edu.my/5079/
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spelling my.um.eprints.50792013-03-14T07:41:02Z http://eprints.um.edu.my/5079/ Epigenetic silencing of CYP24 in tumor-derived endothelial cells contributes to selective growth inhibition by calcitriol Chung, I. Karpf, A.R. Muindi, J.R. Conroy, J.M. Nowak, N.J. Johnson, C.S. Trump, D.L. R Medicine Calcitriol (1,25-dihydroxycholecalciferol), the most active form of vitamin D, has selective anti-proliferative effects on tumor-derived endothelial cells (TDEC) compared with Matrigel-derived endothelial cells (MDEC). Although both cell types have an intact vitamin D receptor-signaling axis, this study demonstrates that upon treatment with calcitriol, 24-hydroxylase (CYP24) mRNA, protein and enzymatic activity were markedly induced in MDEC in a time-dependent manner but not in TDEC. Furthermore, treatment of MDEC with a CYP24 small interfering RNA restored sensitivity to calcitriol. To investigate the lack of CYP24 induction in TDEC, we examined methylation patterns in the promoter regions of the CYP24 gene in these two cell types. We identified two putative CpG island regions located at the 5' end. Using methylation-specific PCR and bisulfite sequencing, we determined that these CpG islands were hypermethylated in TDEC but not in MDEC. These data may explain the recruitment of vitamin D receptor to the promoter region in MDEC but not TDEC, as revealed by chromatin immunoprecipitation analyses. Treatment of TDEC with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine restored calcitriol-mediated induction of CYP24, which led to loss of sensitivity to calcitriol growth inhibitory effects. CYP24 promoter hypermethylation was also observed in endothelial cells isolated from other tumors but not in endothelial cells isolated from normal mouse tissues. These observations indicate that the methylation status of the CYP24 promoter differs in endothelial cells isolated from different microenvironments (tumor versus normal) and that methylation silencing of CYP24 contributes to selective calcitriol-mediated growth inhibition in endothelial cells. 2007 Article PeerReviewed application/pdf en http://eprints.um.edu.my/5079/1/Chung-2007-Epigenetic_silencing.pdf Chung, I. and Karpf, A.R. and Muindi, J.R. and Conroy, J.M. and Nowak, N.J. and Johnson, C.S. and Trump, D.L. (2007) Epigenetic silencing of CYP24 in tumor-derived endothelial cells contributes to selective growth inhibition by calcitriol. Journal of Biological Chemistry, 282 (12). pp. 8704-8714. ISSN 0021-9258
institution Universiti Malaya
building UM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaya
content_source UM Research Repository
url_provider http://eprints.um.edu.my/
language English
topic R Medicine
spellingShingle R Medicine
Chung, I.
Karpf, A.R.
Muindi, J.R.
Conroy, J.M.
Nowak, N.J.
Johnson, C.S.
Trump, D.L.
Epigenetic silencing of CYP24 in tumor-derived endothelial cells contributes to selective growth inhibition by calcitriol
description Calcitriol (1,25-dihydroxycholecalciferol), the most active form of vitamin D, has selective anti-proliferative effects on tumor-derived endothelial cells (TDEC) compared with Matrigel-derived endothelial cells (MDEC). Although both cell types have an intact vitamin D receptor-signaling axis, this study demonstrates that upon treatment with calcitriol, 24-hydroxylase (CYP24) mRNA, protein and enzymatic activity were markedly induced in MDEC in a time-dependent manner but not in TDEC. Furthermore, treatment of MDEC with a CYP24 small interfering RNA restored sensitivity to calcitriol. To investigate the lack of CYP24 induction in TDEC, we examined methylation patterns in the promoter regions of the CYP24 gene in these two cell types. We identified two putative CpG island regions located at the 5' end. Using methylation-specific PCR and bisulfite sequencing, we determined that these CpG islands were hypermethylated in TDEC but not in MDEC. These data may explain the recruitment of vitamin D receptor to the promoter region in MDEC but not TDEC, as revealed by chromatin immunoprecipitation analyses. Treatment of TDEC with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine restored calcitriol-mediated induction of CYP24, which led to loss of sensitivity to calcitriol growth inhibitory effects. CYP24 promoter hypermethylation was also observed in endothelial cells isolated from other tumors but not in endothelial cells isolated from normal mouse tissues. These observations indicate that the methylation status of the CYP24 promoter differs in endothelial cells isolated from different microenvironments (tumor versus normal) and that methylation silencing of CYP24 contributes to selective calcitriol-mediated growth inhibition in endothelial cells.
format Article
author Chung, I.
Karpf, A.R.
Muindi, J.R.
Conroy, J.M.
Nowak, N.J.
Johnson, C.S.
Trump, D.L.
author_facet Chung, I.
Karpf, A.R.
Muindi, J.R.
Conroy, J.M.
Nowak, N.J.
Johnson, C.S.
Trump, D.L.
author_sort Chung, I.
title Epigenetic silencing of CYP24 in tumor-derived endothelial cells contributes to selective growth inhibition by calcitriol
title_short Epigenetic silencing of CYP24 in tumor-derived endothelial cells contributes to selective growth inhibition by calcitriol
title_full Epigenetic silencing of CYP24 in tumor-derived endothelial cells contributes to selective growth inhibition by calcitriol
title_fullStr Epigenetic silencing of CYP24 in tumor-derived endothelial cells contributes to selective growth inhibition by calcitriol
title_full_unstemmed Epigenetic silencing of CYP24 in tumor-derived endothelial cells contributes to selective growth inhibition by calcitriol
title_sort epigenetic silencing of cyp24 in tumor-derived endothelial cells contributes to selective growth inhibition by calcitriol
publishDate 2007
url http://eprints.um.edu.my/5079/1/Chung-2007-Epigenetic_silencing.pdf
http://eprints.um.edu.my/5079/
_version_ 1643687481682427904
score 13.211869

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