衰老样自发性表观遗传沉默促进 Wnt 激活、干性和 Braf 诱导的肿瘤发生。
Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and Braf-Induced Tumorigenesis.
机构信息
CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA.
Hopkins Conte Digestive Disease, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
出版信息
Cancer Cell. 2019 Feb 11;35(2):315-328.e6. doi: 10.1016/j.ccell.2019.01.005.
We addressed the precursor role of aging-like spontaneous promoter DNA hypermethylation in initiating tumorigenesis. Using mouse colon-derived organoids, we show that promoter hypermethylation spontaneously arises in cells mimicking the human aging-like phenotype. The silenced genes activate the Wnt pathway, causing a stem-like state and differentiation defects. These changes render aged organoids profoundly more sensitive than young ones to transformation by Braf, producing the typical human proximal BRAF-driven colon adenocarcinomas characterized by extensive, abnormal gene-promoter CpG-island methylation, or the methylator phenotype (CIMP). Conversely, CRISPR-mediated simultaneous inactivation of a panel of the silenced genes markedly sensitizes to Braf-induced transformation. Our studies tightly link aging-like epigenetic abnormalities to intestinal cell fate changes and predisposition to oncogene-driven colon tumorigenesis.
我们研究了衰老样自发启动子 DNA 高甲基化在引发肿瘤发生中的前导作用。使用源自小鼠结肠的类器官，我们表明，在模拟人类衰老样表型的细胞中，启动子高甲基化自发出现。沉默的基因激活了 Wnt 通路，导致类似干细胞的状态和分化缺陷。这些变化使衰老的类器官比年轻的类器官对 Braf 转化更为敏感，产生典型的人近端 BRAF 驱动的结肠腺癌，其特征是广泛的、异常的基因启动子 CpG 岛甲基化，或甲基化表型（CIMP）。相反，CRISPR 介导的同时失活一组沉默的基因显著增加了对 Braf 诱导的转化的敏感性。我们的研究将衰老样表观遗传异常与肠道细胞命运变化和对致癌基因驱动的结肠肿瘤发生的易感性紧密联系起来。
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