Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity.
Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity.
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DOI：
10.1016/j.cell.2013.06.005
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发表时间：
2013-07-03
期刊：
影响因子：
64.5
通讯作者：
Weinberg RA
中科院分区：
文献类型：
--
作者：
Chaffer CL;Marjanovic ND;Lee T;Bell G;Kleer CG;Reinhardt F;D'Alessio AC;Young RA;Weinberg RA
最近发现，正常和肿瘤上皮细胞重新进入干细胞状态，在癌症发病机制的背景下提出了一个有趣的可能性：癌的侵袭性不是来自其现有的癌症干细胞（CSC）的内容，而是来自其从非CSC群体产生新CSC的倾向。在这里，我们证明了人类基底乳腺癌的非CSC是可塑性细胞群，容易从非CSC状态转换为CSC状态。观察到的细胞可塑性取决于ZEB 1，ZEB 1是上皮-间充质转化的关键调节因子。我们发现塑料非CSC保持ZEB 1启动子在二价染色质配置，使他们能够很容易地响应微环境信号，如TGF β。作为响应，ZEB 1启动子从二价转化为活性染色质构型，ZEB 1转录增加，非CSC随后进入CSC状态。我们的研究结果支持了一个动态模型，其中低和高致瘤状态之间的相互转换频繁发生，从而增加了致瘤性和恶性潜力。
The recent discovery that normal and neoplastic epithelial cells re-enter the stem-cell state raised an intriguing possibility in the context of cancer pathogenesis: the aggressiveness of carcinomas derives not from their existing content of cancer stem cells (CSCs), but from their proclivity to generate new CSCs from non-CSC populations. Here we demonstrate that non-CSCs of human basal breast cancers are plastic cell populations that readily switch from a non-CSC to CSC-state. The observed cell plasticity is dependent on ZEB1, a key regulator of the epithelial-mesenchymal transition. We find plastic non-CSCs maintain the ZEB1 promoter in a bivalent chromatin configuration enabling them to respond readily to microenvironmental signals, such as TGFbeta. In response, the ZEB1 promoter converts from a bivalent to active chromatin configuration, ZEB1 transcription increases and non-CSCs subsequently enter the CSC state. Our findings support a dynamic model where interconversions between low and high tumorigenic states occur frequently, thereby increasing tumorigenic and malignant potential.
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