Epigenetic silencing of CYP24 in the tumor microenvironment

Johnson, C.S. and Chung, I. and Trump, D.L. (2010) Epigenetic silencing of CYP24 in the tumor microenvironment. Journal of Steroid Biochemistry and Molecular Biology, 121 (1-2). pp. 338-342. ISSN 0960-0760,

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Abstract

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. (C) 2010 Elsevier Ltd. All rights reserved.

Item Type: Article
Funders: UNSPECIFIED
Additional Information: Johnson, Candace S. Chung, Ivy Trump, Donald L. 14th Workshop on Vitamin D Oct 04-08, 2009 Burgge, BELGIUM Si
Uncontrolled Keywords: Calcitriol, vitamin D, tumor derived endothelial cells, matrigel-derived endothelial cells, CYP 24
Subjects: R Medicine
Divisions: Faculty of Medicine
Depositing User: Ms azrahani halim
Date Deposited: 18 Mar 2013 01:28
Last Modified: 18 Mar 2013 01:28
URI: http://eprints.um.edu.my/id/eprint/5077

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