Concordant epigenetic silencing of transforming growth factor-β signaling pathway genes occurs early in breast carcinogenesis
Concordant epigenetic silencing of transforming growth factor-β signaling pathway genes occurs early in breast carcinogenesis
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DOI：
10.1158/0008-5472.can-07-1284
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发表时间：
2007-12-15
期刊：
影响因子：
11.2
通讯作者：
Clark, Susan J.
中科院分区：
文献类型：
--
作者：
Hinshelwood, Rebecca A.;Huschtscha, Lily I.;Clark, Susan J.
在标准细胞培养条件下生长的人乳腺上皮细胞（HMEC）进入一个被称为选择的生长阶段，但一个亚群能够逃脱抑制并继续增殖。这些细胞被称为后选择或变异HMECs，可能来源于正常乳腺上皮中发现的随后获得癌前病变的前体细胞，包括p16（INK4A）启动子超甲基化。肿瘤抑制基因通过DNA甲基化和组蛋白修饰的表观遗传沉默是肿瘤发生的早期事件。一个主要的挑战是找到通常沉默的基因或基因通路，以提供早期表观遗传诊断和治疗癌症的靶点。为了确定乳腺癌中发生的早期表观遗传事件，我们使用微阵列筛选在选择后HMECs中被抑制但在用去甲基化剂5-aza-2'-脱氧胞苷治疗后重新激活的基因通路。我们发现，在选择后的HMEC群体中，转化生长因子β (tgf - β)信号通路的几个成员持续下调，这与Smad4核染色的显著降低有关。基因抑制与DNA甲基化无关，但与染色质重塑有关，包括组蛋白H3赖氨酸27三甲基化减少，组蛋白H3赖氨酸9二甲基化和去乙酰化增加。这些结果首次表明，tgf - β 2及其受体tgf - β R1和tgf - β R2以及血小板反应蛋白-1激活剂在乳腺癌发生早期通过组蛋白修饰一致抑制，表明tgf - β信号通路是表观遗传疗法激活基因的新靶点。
Human mammary epithelial cells (HMEC) grown under standard cell culture conditions enter a growth phase referred to as selection, but a subpopulation is able to escape from arrest and continue to proliferate. These cells, called post-selection or variant HMECs, may be derived from progenitor cells found in normal mammary epithelium that subsequently acquire premalignant lesions, including p16(INK4A) promoter hypermethylation. Epigenetic silencing of tumor suppressor genes through DNA methylation and histone modification is an early event in tumorigenesis. A major challenge is to find genes or gene pathways that are commonly silenced to provide 9 early epigenetic diagnostic and therapeutic cancer targets. To identify very early epigenetic events that occur in breast cancer, we used microarrays to screen for gene pathways that were suppressed in post-selection HMECs but reactivated after treatment with the demethylation agent 5-aza-2'-deoxycytidine. We found that several members of the transforming growth factor beta (TGF-beta) signaling pathway were consistently down-regulated in the post-selection HMEC populations, and this was associated with a marked decrease in Smad4 nuclear staining. Gene suppression was not associated with DNA methylation but with chromatin remodeling, involving a decrease in histone H3 lysine 27 trimethylation and an increase in histone H3 lysine 9 dimethylation and deacetylation. These results show for the first time that TGF-beta 2, its receptors TGF-beta R1 and TGF-beta R2, and activator thrombospondin-1 are concordantly suppressed early in breast carcinogenesis by histone modifications and indicate that the TGF-beta signaling pathway is a novel target for gene activation by epigenetic therapy.