Altered Ten Eleven Translocation Methylcytosine Dioxygenase Expression and DNA Hydroxymethylation in a Mouse Model of Prostate Cancer.

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Prostate Pub Date : 2025-08-01 Epub Date: 2025-05-11 DOI:10.1002/pros.24912

Matthew Aguilera, David L Klinkebiel, Victoryn Williams, Jeffrey Rovatti, Benjamin Purizhansky, Barbara A Foster, Adam R Karpf, Shannon R M Kinney

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引用次数: 0

Abstract

Background: DNA hydroxymethylation (5hmC) is known to be altered in human prostate cancer. An animal model is required to study the functional roles of the ten eleven translocation (TET) DNA dioxygenases and the 5hmC modification in prostate cancer development and progression.

Methods: We characterized Tet expression, global genomic 5hmC, and genome-wide 5hmC patterns, and the transcriptome, in the TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) autochthonous model of prostate cancer.

Results: We observed increased mRNA and protein levels of Tet1 in TRAMP samples, as compared to normal mouse prostate. Additionally, we found minimal expression of Tet2 mRNA overall, and Tet3 mRNA levels appeared similar in both sample types. However, TRAMP tumors expressed what appeared to be the inactive form of Tet3, versus the active form expressed in normal prostates. TRAMP tumors displayed global genomic hypohydroxymethylation (i.e., loss of 5hmC), and genome-wide analysis revealed widespread hypohydroxymethylation was interspersed with regions of locus-specific hyperhydroxymethylation (i.e., increased 5hmC). The differentially hydroxymethylated regions correlated with altered gene expression, and pathway analyses indicated that these genes often participate in oncogenic pathways.

Conclusions: Tet expression and 5hmC patterns are altered in the TRAMP model and closely match what has been observed in human prostate cancer, suggesting that TRAMP is a suitable model to study the role of Tets and 5hmC in prostate cancer development and progression.

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前列腺癌小鼠模型中10 - 11易位甲基胞嘧啶双加氧酶表达和DNA羟甲基化的改变。

背景：DNA羟甲基化（5hmC）已知在人类前列腺癌中发生改变。研究TET DNA双加氧酶和5hmC修饰在前列腺癌发生发展中的功能作用，需要建立动物模型。方法：在转基因小鼠前列腺腺癌（TRAMP）原位前列腺癌模型中，我们对Tet表达、全基因组5hmC和全基因组5hmC模式以及转录组进行了表征。结果：与正常小鼠前列腺相比，我们观察到TRAMP样品中Tet1 mRNA和蛋白水平升高。此外，我们发现Tet2 mRNA的总体表达量最低，两种样品类型的Tet3 mRNA水平相似。然而，与正常前列腺中表达的活性形式相比，TRAMP肿瘤表达的似乎是无活性形式的Tet3。TRAMP肿瘤表现为全基因组低羟甲基化（即5hmC缺失），全基因组分析显示，广泛的低羟甲基化与位点特异性高羟甲基化（即5hmC增加）区域穿插。差异羟甲基化区域与基因表达改变相关，通路分析表明这些基因经常参与致癌途径。结论：Tet表达和5hmC模式在TRAMP模型中发生改变，与在人类前列腺癌中观察到的结果非常吻合，提示TRAMP是研究Tet和5hmC在前列腺癌发生发展中的作用的合适模型。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Prostate 医学-泌尿学与肾脏学

CiteScore

5.10

自引率

3.60%

发文量

180

审稿时长

1.5 months

期刊介绍： The Prostate is a peer-reviewed journal dedicated to original studies of this organ and the male accessory glands. It serves as an international medium for these studies, presenting comprehensive coverage of clinical, anatomic, embryologic, physiologic, endocrinologic, and biochemical studies.