DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation
DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation
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DOI：
10.1038/cdd.2013.202
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发表时间：
2014-05-01
影响因子：
12.4
通讯作者：
Maitland, N. J.
中科院分区：
文献类型：
--
作者：
Pellacani, D.;Kestoras, D.;Maitland, N. J.
前列腺癌（CaP）主要由管腔样分化细胞组成，但含有少量基底细胞亚群（包括干细胞样细胞），其可增殖并分化为管腔样细胞。在癌症中，CpG岛高甲基化与基因下调有关，但这两种现象之间的因果关系仍有争议。在这里，我们通过分析癌症中分离的基底细胞和腔细胞，在癌细胞层次结构和上皮分化的背景下阐明了CaP中CpG岛超甲基化的起源和功能。对于CaP中高甲基化的一组基因（包括GSTP1），基因下调是细胞分化的结果，并且不是癌症特异性的。然而，在分化程度更高的癌细胞中观察到超甲基化，并且超增殖促进了超甲基化。这些基因在未分化的CaP细胞中保持活跃表达和无甲基化，并且它们的超甲基化对于肿瘤的发展或扩张不是必需的。我们目前的证据的原因和动力学的CpG岛高甲基化的CaP，显示，对于一组特定的基因，启动子甲基化是下游的基因下调，并不是一个驱动程序的基因抑制，而基因抑制是组织特异性分化的结果。
Prostate cancer (CaP) is mostly composed of luminal-like differentiated cells, but contains a small subpopulation of basal cells (including stem-like cells), which can proliferate and differentiate into luminal-like cells. In cancers, CpG island hypermethylation has been associated with gene downregulation, but the causal relationship between the two phenomena is still debated. Here we clarify the origin and function of CpG island hypermethylation in CaP, in the context of a cancer cell hierarchy and epithelial differentiation, by analysis of separated basal and luminal cells from cancers. For a set of genes (including GSTP1) that are hypermethylated in CaP, gene downregulation is the result of cell differentiation and is not cancer specific. Hypermethylation is however seen in more differentiated cancer cells and is promoted by hyperproliferation. These genes are maintained as actively expressed and methylation-free in undifferentiated CaP cells, and their hypermethylation is not essential for either tumour development or expansion. We present evidence for the causes and the dynamics of CpG island hypermethylation in CaP, showing that, for a specific set of genes, promoter methylation is downstream of gene downregulation and is not a driver of gene repression, while gene repression is a result of tissue-specific differentiation.