Immortality, but not oncogenic transformation, of primary human cells leads to epigenetic reprogramming of DNA methylation and gene expression.
Immortality, but not oncogenic transformation, of primary human cells leads to epigenetic reprogramming of DNA methylation and gene expression.
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DOI：
10.1093/nar/gkt1351
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发表时间：
2014-04
影响因子：
14.9
通讯作者：
Stancheva I
中科院分区：
文献类型：
--
作者：
Gordon K;Clouaire T;Bao XX;Kemp SE;Xenophontos M;de Las Heras JI;Stancheva I
正常细胞向癌症的致癌转化通常包括几个步骤，导致获得无限的生长潜力，逃避凋亡和对生长抑制信号无反应。遗传和表观遗传变化都可能导致癌症的发生和发展。鉴于人类癌症的巨大遗传异质性和体内监测癌症启动事件的困难，获得基因突变和转化细胞表观遗传变化的时间进展之间的确切关系在很大程度上尚不清楚。在这里，我们使用体外模型系统来研究原代人类细胞的细胞永生和致癌转化对DNA甲基化和基因表达的表观遗传重编程的贡献。我们的数据表明，细胞复制寿命的延长足以诱导基因启动子上DNA甲基化的积累，并以时间依赖的方式导致基因表达的大规模变化。相反，在永生化细胞中持续表达协同癌基因，虽然对锚定非依赖性生长和避免凋亡是必不可少的，但并不影响启动子上的从头DNA甲基化，并诱导微妙的表达变化。综上所述，这些观察表明，细胞永生促进表观遗传适应高度增殖状态，而转化的癌基因赋予转化的人类细胞额外的特性。
Tumourigenic transformation of normal cells into cancer typically involves several steps resulting in acquisition of unlimited growth potential, evasion of apoptosis and non-responsiveness to growth inhibitory signals. Both genetic and epigenetic changes can contribute to cancer development and progression. Given the vast genetic heterogeneity of human cancers and difficulty to monitor cancer-initiating events in vivo, the precise relationship between acquisition of genetic mutations and the temporal progression of epigenetic alterations in transformed cells is largely unclear. Here, we use an in vitro model system to investigate the contribution of cellular immortality and oncogenic transformation of primary human cells to epigenetic reprogramming of DNA methylation and gene expression. Our data demonstrate that extension of replicative life span of the cells is sufficient to induce accumulation of DNA methylation at gene promoters and large-scale changes in gene expression in a time-dependent manner. In contrast, continuous expression of cooperating oncogenes in immortalized cells, although essential for anchorage-independent growth and evasion of apoptosis, does not affect de novo DNA methylation at promoters and induces subtle expression changes. Taken together, these observations imply that cellular immortality promotes epigenetic adaptation to highly proliferative state, whereas transforming oncogenes confer additional properties to transformed human cells.
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影响因子：
11.2
作者：
Fackler MJ;Umbricht CB;Williams D;Argani P;Cruz LA;Merino VF;Teo WW;Zhang Z;Huang P;Visvananthan K;Marks J;Ethier S;Gray JW;Wolff AC;Cope LM;Sukumar S
通讯作者：
Sukumar S
影响因子：
50.3
作者：
De Carvalho DD;Sharma S;You JS;Su SF;Taberlay PC;Kelly TK;Yang X;Liang G;Jones PA
通讯作者：
Jones PA
影响因子：
30.8
作者：
Landan, Gilad;Cohen, Netta Mendelson;Tanay, Amos
通讯作者：
Tanay, Amos
影响因子：
7
作者：
Hinoue, Toshinori;Weisenberger, Daniel J.;Laird, Peter W.
通讯作者：
Laird, Peter W.
影响因子：
7
作者：
Hon, Gary C.;Hawkins, R. David;Ren, Bing
通讯作者：
Ren, Bing