Epigenetic silencing of CYP24 in the tumor microenvironment.
Epigenetic silencing of CYP24 in the tumor microenvironment.
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DOI：
10.1016/j.jsbmb.2010.03.046
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发表时间：
2010-07
影响因子：
4.1
通讯作者：
Trump, Donald L.
中科院分区：
文献类型：
--
作者：
Johnson, Candace S.;Chung, Ivy;Trump, Donald L.
骨化三醇（1，25二羟基胆钙化醇）在体外和体内许多肿瘤模型系统中具有显著的抗肿瘤活性。我们开发了一种从肿瘤和Matrigel环境中分离新鲜内皮细胞的系统，该系统表明参与维生素D信号传导的分解代谢酶CYP 24在肿瘤衍生的内皮细胞（TDEC）中选择性地表观遗传沉默。TDEC保持与分离自正常组织和基质胶塞（MDEC）的内皮细胞不同的表型特征。在TDEC中，骨化三醇诱导G 0/G1期阻滞，调节p27和p21，诱导凋亡性细胞死亡并降低P-Erk和P-Akt。相反，从正常组织和MDEC分离的内皮细胞对骨化三醇介导的抗增殖作用无反应，尽管通过维生素D受体（VDR）的信号传导完整。在对骨化三醇敏感的TDEC中，CYP 24启动子位于5′端的两个CpG岛区域发生高甲基化，这种高甲基化可能有助于CYP 24的基因沉默。MDEC中这两个区域的甲基化程度显著较低。最后，用DNA甲基转移酶抑制剂治疗TDEC可恢复骨化三醇介导的CYP 24诱导和对骨化三醇的耐药性。这些数据表明，CYP 24的表观遗传沉默调节细胞对骨化三醇的反应。
Calcitriol (1,25 dihydroxycholecalciferol) has significant antitumor 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 G0/G1 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 is 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.
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影响因子：
2.1
作者：
Getzenberg, RH;Light, BW;Johnson, CS
通讯作者：
Johnson, CS
影响因子：
7.4
作者：
Grover, AC;Tangrea, MA;Libutti, SK
通讯作者：
Libutti, SK
影响因子：
3.5
作者：
Alagbala, Adebusola A.;Johnson, Candace S.;Foster, Barbara A.
通讯作者：
Foster, Barbara A.
影响因子：
30.8
作者：
Hu, M;Yao, J;Polyak, K
通讯作者：
Polyak, K
影响因子：
4.8
作者：
Chung, Ivy;Karpf, Adam R.;Trump, Donald L.
通讯作者：
Trump, Donald L.