Mammalian cells acquire epigenetic hallmarks of human cancer during immortalization.
Mammalian cells acquire epigenetic hallmarks of human cancer during immortalization.
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DOI：
10.1093/nar/gks1051
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发表时间：
2013-01-07
影响因子：
14.9
通讯作者：
Besaratinia A
中科院分区：
文献类型：
--
作者：
Tommasi S;Zheng A;Weninger A;Bates SE;Li XA;Wu X;Hollstein M;Besaratinia A
恶性进展需要细胞克服衰老并转变为永生表型。因此，探索衰老/永生化过程中发生的遗传和表观遗传变化可能有助于阐明导致细胞转化的关键事件。在本研究中，我们已经全面剖析了DNA甲基化与原代、衰老和永生化小鼠胚胎成纤维细胞基因表达的关系。使用高分辨率全基因组定位技术，然后进行广泛的位点特异性验证试验，我们已经确定了24个CpG岛，与原代鼠成纤维细胞相比，在永生化细胞系中显示出显著更高水平的CpG甲基化。这些高甲基化的CpG岛中的几个与参与MEK-ERK途径的基因相关，MEK-ERK途径是癌症中最常被破坏的途径之一。大约一半的高甲基化靶点是发育调节因子，并且通常在小鼠胚胎干细胞中的二价染色质的背景下与抑制性Polycomb组（PcG）蛋白结合。由于PcG相关的异常DNA甲基化是几种人类恶性肿瘤的标志，我们的甲基化数据表明，多能性基因的表观遗传重编程可能会启动细胞永生化。与甲基化改变一致，全局基因表达分析揭示，细胞永生化过程中失调的绝大多数基因属于会聚到MEK-ERK途径的基因家族。此外，MAP激酶网络的几个失调成员显示伴随的CpG岛高甲基化。解开细胞永生化的替代表观遗传途径对于理解导致细胞转化的关键事件至关重要。与遗传改变不同，表观遗传变化是可逆的事件，因此，可以接受药物干预，这使得它们在遗传方法证明不充分时成为癌症治疗的吸引人的靶点。
Progression to malignancy requires that cells overcome senescence and switch to an immortal phenotype. Thus, exploring the genetic and epigenetic changes that occur during senescence/immortalization may help elucidate crucial events that lead to cell transformation. In the present study, we have globally profiled DNA methylation in relation to gene expression in primary, senescent and immortalized mouse embryonic fibroblasts. Using a high-resolution genome-wide mapping technique, followed by extensive locus-specific validation assays, we have identified 24 CpG islands that display significantly higher levels of CpG methylation in immortalized cell lines as compared to primary murine fibroblasts. Several of these hypermethylated CpG islands are associated with genes involved in the MEK–ERK pathway, one of the most frequently disrupted pathways in cancer. Approximately half of the hypermethylated targets are developmental regulators, and bind to the repressive Polycomb group (PcG) proteins, often in the context of bivalent chromatin in mouse embryonic stem cells. Because PcG-associated aberrant DNA methylation is a hallmark of several human malignancies, our methylation data suggest that epigenetic reprogramming of pluripotency genes may initiate cell immortalization. Consistent with methylome alterations, global gene expression analysis reveals that the vast majority of genes dysregulated during cell immortalization belongs to gene families that converge into the MEK–ERK pathway. Additionally, several dysregulated members of the MAP kinase network show concomitant hypermethylation of CpG islands. Unlocking alternative epigenetic routes for cell immortalization will be paramount for understanding crucial events leading to cell transformation. Unlike genetic alterations, epigenetic changes are reversible events, and as such, can be amenable to pharmacological interventions, which makes them appealing targets for cancer therapy when genetic approaches prove inadequate.
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影响因子：
78.5
作者：
Collado, Manuel;Serrano, Manuel
通讯作者：
Serrano, Manuel
影响因子：
3.7
作者：
Coppé JP;Patil CK;Rodier F;Krtolica A;Beauséjour CM;Parrinello S;Hodgson JG;Chin K;Desprez PY;Campisi J
通讯作者：
Campisi J
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
DOI：
10.4161/cc.7.17.6522
发表时间：
2008-09-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Glazer RI;Wang XY;Yuan H;Yin Y
通讯作者：
Yin Y
影响因子：
4.3
作者：
Feng, Lijin;Hollstein, Monica;Xu, Yang
通讯作者：
Xu, Yang