Epigenetic dysregulation of key developmental genes in radiation-induced rat mammary carcinomas
Epigenetic dysregulation of key developmental genes in radiation-induced rat mammary carcinomas
复制标题
DOI：
10.1002/ijc.31309
复制
发表时间：
2018-07-15
影响因子：
6.4
通讯作者：
Kakinuma, Shizuko
中科院分区：
文献类型：
--
作者：
Daino, Kazuhiro;Nishimura, Mayumi;Kakinuma, Shizuko
随着全球癌症长期幸存者数量的增加，人们越来越担心放疗诱发继发性癌症的风险。与致癌相关的基因的表观遗传修饰由于其可逆性而成为预防癌症的有吸引力的目标。为了识别辐射暴露诱发的乳腺癌中功能相关 DNA 甲基化模式可能发生变化的基因，我们对伽马射线诱发的大鼠乳腺癌和正常乳腺进行了基于微阵列的整体 DNA 甲基化和表达谱分析。基因表达谱鉴定了肿瘤中发育相关基因的失调，包括多梳抑制复合物 2 (PRC2) 的下游靶标和 zeste 同源物 2 增强子（PRC2 的一个组成部分）的过度表达。通过整合表达和 DNA 甲基化谱，我们鉴定了 10 个高甲基化基因和 3 个低甲基化基因，它们可能充当肿瘤抑制基因和由于异常 DNA 甲基化而失调的癌基因；这些基因中有一半编码发育转录因子。亚硫酸氢盐测序和定量 PCR 证实了多梳调控的发育相关转录因子基因 Dmrt2、Hoxa7、Foxb1、Sox17、Lhx8、Gata3 和 Runx1 的失调。通过免疫组织化学进一步验证了 Hoxa7 的沉默。这些结果表明，在辐射诱发的乳腺癌中，PRC2 介导的异常 DNA 甲基化导致发育相关转录因子基因的失调。我们的研究结果为连接表观遗传调控和辐射诱发乳腺癌发生的分子机制提供了线索，并强调了这种表观遗传机制作为癌症预防目标的潜力。有什么新鲜事？放疗后继发性癌症的发展越来越引起长期癌症幸存者的关注。在这里，作者检查了辐射诱发的大鼠乳腺癌的表观遗传标记。他们发现多梳抑制复合物2介导的发育相关转录因子编码基因的异常DNA甲基化以及随后在致癌过程中下游基因靶标的失调，强调了表观遗传学在二级癌症预防中的潜力。
With the increase in the number of long-term cancer survivors worldwide, there is a growing concern about the risk of secondary cancers induced by radiotherapy. Epigenetic modifications of genes associated with carcinogenesis are attractive targets for the prevention of cancer owing to their reversible nature. To identify genes with possible changes in functionally relevant DNA methylation patterns in mammary carcinomas induced by radiation exposure, we performed microarray-based global DNA methylation and expression profiling in gamma-ray-induced rat mammary carcinomas and normal mammary glands. The gene expression profiling identified dysregulation of developmentally related genes, including the downstream targets of polycomb repressive complex 2 (PRC2) and overexpression of enhancer of zeste homolog 2, a component of PRC2, in the carcinomas. By integrating expression and DNA methylation profiles, we identified ten hypermethylated and three hypomethylated genes that possibly act as tumor-suppressor genes and oncogenes dysregulated by aberrant DNA methylation; half of these genes encode developmental transcription factors. Bisulfite sequencing and quantitative PCR confirmed the dysregulation of the polycomb-regulated developmentally related transcription-factor genes Dmrt2, Hoxa7, Foxb1, Sox17, Lhx8, Gata3 and Runx1. Silencing of Hoxa7 was further verified by immunohistochemistry. These results suggest that, in radiation-induced mammary gland carcinomas, PRC2-mediated aberrant DNA methylation leads to dysregulation of developmentally related transcription-factor genes. Our findings provide clues to molecular mechanisms linking epigenetic regulation and radiation-induced breast carcinogenesis and underscore the potential of such epigenetic mechanisms as targets for cancer prevention.What's new?Development of a secondary cancer after radiotherapy is of growing concern for long-term cancer survivors. Here the authors examined epigenetic marks in radiation-induced rat mammary carcinomas. They found polycomb repressive complex 2-mediated aberrant DNA methylation of developmentally relevant transcription factor-encoding genes and a consequent dysregulation of downstream gene targets during carcinogenesis, underscoring the potential of epigenetics in secondary cancer prevention.