追踪前列腺癌中的 TET1 表达：发现具有明显致癌特征的恶性细胞。

Tracing TET1 expression in prostate cancer: discovery of malignant cells with a distinct oncogenic signature.

机构信息

Clinic of Urology, Pediatric Urology and Andrology, Justus-Liebig-University Giessen, Giessen, Germany.

Working Group Epigenetics of Urogenital System, Clinic of Urology, Pediatric Urology and Andrology, Justus-Liebig-University Giessen, Giessen, Germany.

出版信息

Clin Epigenetics. 2021 Nov 29;13(1):211. doi: 10.1186/s13148-021-01201-7.

DOI:10.1186/s13148-021-01201-7

PMID:34844636

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8630881/

Abstract

BACKGROUND

Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) is involved in DNA demethylation and transcriptional regulation, plays a key role in the maintenance of stem cell pluripotency, and is dysregulated in malignant cells. The identification of cancer stem cells (CSCs) driving tumor growth and metastasis is the primary objective of biomarker discovery in aggressive prostate cancer (PCa). In this context, we analyzed TET1 expression in PCa.

METHODS

A large-scale immunohistochemical analysis of TET1 was performed in normal prostate (NOR) and PCa using conventional slides (50 PCa specimens) and tissue microarrays (669 NOR and 1371 PCa tissue cores from 371 PCa specimens). Western blotting, RT-qPCR, and 450 K methylation array analyses were performed on PCa cell lines. Genome-wide correlation, gene regulatory network, and functional genomics studies were performed using publicly available data sources and bioinformatics tools.

RESULTS

In NOR, TET1 was exclusively expressed in normal cytokeratin 903 (CK903)-positive basal cells. In PCa, TET1 was frequently detected in alpha-methylacyl-CoA racemase (AMACR)-positive tumor cell clusters and was detectable at all tumor stages and Gleason scores. Pearson's correlation analyses of PCa revealed 626 TET1-coactivated genes (r > 0.5) primarily encoding chromatin remodeling and mitotic factors. Moreover, signaling pathways regulating antiviral processes (62 zinc finger, ZNF, antiviral proteins) and the pluripotency of stem cells were activated. A significant proportion of detected genes exhibited TET1-correlated promoter hypomethylation. There were 161 genes encoding transcription factors (TFs), of which 133 were ZNF-TFs with promoter binding sites in TET1 and in the vast majority of TET1-coactivated genes.

CONCLUSIONS

TET1-expressing cells are an integral part of PCa and may represent CSCs with oncogenic potential.

摘要

背景

十-十一易位甲基胞嘧啶双加氧酶 1（TET1）参与 DNA 去甲基化和转录调控，在维持干细胞多能性方面发挥关键作用，并在恶性细胞中失调。鉴定驱动肿瘤生长和转移的癌症干细胞（CSC）是侵袭性前列腺癌（PCa）生物标志物发现的首要目标。在这种情况下，我们分析了 PCa 中的 TET1 表达。

方法

使用常规载玻片（50 例 PCa 标本）和组织微阵列（来自 371 例 PCa 标本的 669 例 NOR 和 1371 例 PCa 组织芯）对 TET1 进行了大规模的免疫组织化学分析。对 PCa 细胞系进行了 Western blot、RT-qPCR 和 450K 甲基化阵列分析。使用公开可用的数据源和生物信息学工具进行了全基因组相关性、基因调控网络和功能基因组学研究。

结果

在 NOR 中，TET1 仅在正常细胞角蛋白 903（CK903）阳性基底细胞中表达。在 PCa 中，TET1 经常在 alpha-methylacyl-CoA racemase（AMACR）阳性肿瘤细胞簇中检测到，并且在所有肿瘤阶段和 Gleason 评分中均可检测到。PCa 的 Pearson 相关性分析显示了 626 个与 TET1 共同激活的基因（r>0.5），主要编码染色质重塑和有丝分裂因子。此外，调节抗病毒过程（62 个锌指、ZNF、抗病毒蛋白）和干细胞多能性的信号通路被激活。检测到的基因中有很大一部分表现出与 TET1 相关的启动子低甲基化。有 161 个基因编码转录因子（TFs），其中 133 个是 ZNF-TFs，其启动子结合位点在 TET1 中，并且在绝大多数 TET1 共同激活的基因中。