Deficiency of the Polycomb Protein RYBP and TET Methylcytosine Oxidases Promotes Extensive CpG Island Hypermethylation and Malignant Transformation.
Deficiency of the Polycomb Protein RYBP and TET Methylcytosine Oxidases Promotes Extensive CpG Island Hypermethylation and Malignant Transformation.
复制标题
DOI：
10.1158/0008-5472.can-23-0269
复制
发表时间：
2023-08-01
期刊：
影响因子：
11.2
通讯作者：
中科院分区：
文献类型：
--
作者：
多梳成分RYBP的功能障碍与5-甲基胞嘧啶氧化酶的缺失共同促进了支气管细胞中CpG岛的广泛超甲基化，并诱导了肿瘤的发生，类似于人类肺部肿瘤的变化。CpG岛的高甲基化(CGI)是癌细胞的共同特征，主要影响多梳相关的基因组区域。阐明导致人类癌症DNA高甲基化的潜在机制有助于确定化学预防策略。在这里，我们评估了多梳复合体和5-甲基胞嘧啶(5mC)氧化酶在保护CGI免受DNA甲基化方面的作用，并观察到编码多梳抑制复合体1(PRC1)组件的四个基因在肿瘤中下调。RYBP是不同PRC1复合体的关键激活因子，在非致癌的支气管上皮细胞中，RYBP与所有三种5mC氧化酶(Tet蛋白)一起失活，导致影响近4,000个靶基因的Polycomb标记CGI广泛高甲基化，这与在人类鳞状细胞肺肿瘤中观察到的DNA高甲基化情况非常相似。RYBP和Tet缺陷细胞表现出与甲基化相关的癌症相关通路的异常调节，包括河马肿瘤抑制网络的缺陷。值得注意的是，四重基因敲除细胞获得了一种转化的表型，包括小鼠的非锚定生长和鳞状细胞癌的形成。这项工作提供了一种促进CGI超甲基化的机制，并表明这种超甲基化可以导致细胞转化。双管齐下的保护机制的崩溃可能是导致肿瘤中CGI基因高甲基化的一条途径。多梳成分RYBP的功能障碍与5-甲基胞嘧啶氧化酶的缺失共同促进了支气管细胞中CpG岛的广泛超甲基化，并诱导了肿瘤的发生，类似于人类肺部肿瘤的变化。
Dysfunction of the Polycomb component RYBP in combination with loss of 5-methylcytosine oxidases promotes widespread hypermethylation of CpG islands in bronchial cells and induces tumorigenesis, resembling changes seen in human lung tumors. Hypermethylation of CpG islands (CGI) is a common feature of cancer cells and predominantly affects Polycomb-associated genomic regions. Elucidating the underlying mechanisms leading to DNA hypermethylation in human cancer could help identify chemoprevention strategies. Here, we evaluated the role of Polycomb complexes and 5-methylcytosine (5mC) oxidases in protecting CGIs from DNA methylation and observed that four genes coding for components of Polycomb repressive complex 1 (PRC1) are downregulated in tumors. Inactivation of RYBP, a key activator of variant PRC1 complexes, in combination with all three 5mC oxidases (TET proteins) in nontumorigenic bronchial epithelial cells led to widespread hypermethylation of Polycomb-marked CGIs affecting almost 4,000 target genes, which closely resembled the DNA hypermethylation landscape observed in human squamous cell lung tumors. The RYBP- and TET-deficient cells showed methylation-associated aberrant regulation of cancer-relevant pathways, including defects in the Hippo tumor suppressor network. Notably, the quadruple knockout cells acquired a transformed phenotype, including anchorage-independent growth and formation of squamous cell carcinomas in mice. This work provides a mechanism promoting hypermethylation of CGIs and shows that such hypermethylation can lead to cell transformation. The breakdown of a two-pronged protection mechanism can be a route towards genome-wide hypermethylation of CGIs in tumors. Dysfunction of the Polycomb component RYBP in combination with loss of 5-methylcytosine oxidases promotes widespread hypermethylation of CpG islands in bronchial cells and induces tumorigenesis, resembling changes seen in human lung tumors.