Aberrant promoter CpG methylation is a mechanism for impaired PHD3 expression in a diverse set of malignant cells.
Aberrant promoter CpG methylation is a mechanism for impaired PHD3 expression in a diverse set of malignant cells.
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DOI：
10.1371/journal.pone.0014617
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发表时间：
2011-01-28
期刊：
影响因子：
3.7
通讯作者：
Domann FE
中科院分区：
文献类型：
--
作者：
Place TL;Fitzgerald MP;Venkataraman S;Vorrink SU;Case AJ;Teoh ML;Domann FE
脯氨酰羟化酶结构域家族（PHD 1 -3）通过负性调节HIF-α蛋白在细胞缺氧反应中起重要作用。这一过程的中断可导致促进肿瘤发生的因子的上调。我们观察到PHD 3在前列腺癌组织和代表不同来源组织的肿瘤细胞系中的基础表达降低。此外，当引入到缺氧环境中时，一些癌细胞系显示PHD 3 mRNA诱导失败。本研究探讨了恶性肿瘤在缺氧条件下既不表达PHD 3也不诱导PHD 3的机制。使用亚硫酸氢盐测序和甲基化DNA富集程序，我们鉴定了前列腺癌、乳腺癌、黑色素瘤和肾癌细胞系中的人PHD 3启动子高甲基化。相比之下，非转化的人前列腺和乳腺上皮细胞系含有未甲基化的PHD 3 CpG岛，并通过上调PHD 3 mRNA正常响应缺氧。仅用去甲基化药物5-氮杂-2 ′-脱氧胞苷处理含有PHD 3启动子高甲基化的细胞系显著增加PHD 3的表达。我们的结论是，PHD 3的表达是沉默的异常CpG甲基化的PHD 3启动子在不同来源的人癌细胞系的子集，这种异常的胞嘧啶甲基化状态是这些癌细胞系未能上调PHD 3 mRNA的机制。我们进一步表明，PHD 3表达的缺失与HIF-1α蛋白水平的增加或HIF转录活性的增加无关，这表明PHD 3的缺失可能通过影响HIF以外的途径在某些癌症中传递选择性优势。
The prolyl-hydroxylase domain family of enzymes (PHD1-3) plays an important role in the cellular response to hypoxia by negatively regulating HIF-α proteins. Disruption of this process can lead to up-regulation of factors that promote tumorigenesis. We observed decreased basal expression of PHD3 in prostate cancer tissue and tumor cell lines representing diverse tissues of origin. Furthermore, some cancer lines displayed a failure of PHD3 mRNA induction when introduced to a hypoxic environment. This study explores the mechanism by which malignancies neither basally express PHD3 nor induce PHD3 under hypoxic conditions. Using bisulfite sequencing and methylated DNA enrichment procedures, we identified human PHD3 promoter hypermethylation in prostate, breast, melanoma and renal carcinoma cell lines. In contrast, non-transformed human prostate and breast epithelial cell lines contained PHD3 CpG islands that were unmethylated and responded normally to hypoxia by upregulating PHD3 mRNA. Only treatment of cells lines containing PHD3 promoter hypermethylation with the demethylating drug 5-aza-2′-deoxycytidine significantly increased the expression of PHD3. We conclude that expression of PHD3 is silenced by aberrant CpG methylation of the PHD3 promoter in a subset of human carcinoma cell lines of diverse origin and that this aberrant cytosine methylation status is the mechanism by which these cancer cell lines fail to upregulate PHD3 mRNA. We further show that a loss of PHD3 expression does not correlate with an increase in HIF-1α protein levels or an increase in the transcriptional activity of HIF, suggesting that loss of PHD3 may convey a selective advantage in some cancers by affecting pathway(s) other than HIF.
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影响因子：
56.9
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1016/j.biocel.2007.01.020
发表时间：
2008-01-01
影响因子：
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作者：
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通讯作者：
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