Interference with Sin3 function induces epigenetic reprogramming and differentiation in breast cancer cells
Interference with Sin3 function induces epigenetic reprogramming and differentiation in breast cancer cells
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DOI：
10.1073/pnas.1006737107
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发表时间：
2010-06-29
影响因子：
11.1
通讯作者：
Waxman, Samuel
中科院分区：
文献类型：
--
作者：
Farias, Eduardo F.;Petrie, Kevin;Waxman, Samuel
Sin 3A/B是一种主要的转录支架和辅阻遏物，在基因转录调控和染色质结构维持中起重要作用，其不适当的募集与肿瘤中异常的基因沉默有关。Sin 3A/B是高度相关的、大的、多域的蛋白质，其与多种转录因子和辅阻遏物组分相互作用，并且我们研究了特定域的功能的破坏是否会导致表观遗传重编程和特定基因子集的去阻遏。为此，我们选择了Sin 3A/B配对的两亲性α-螺旋（PAH 2）结构域的基础上，其建立的作用，介导的影响，相对较少的转录因子含有PAH 2结合基序称为Sin 3相互作用结构域（SID）。在这里，我们表明，在人类和小鼠乳腺癌细胞中，通过引入SID诱饵干扰PAH 2与含SID的伴侣蛋白的结合来靶向破坏Sin 3功能，从而逆转了参与细胞生长和分化的基因的沉默。特别是，SID诱饵导致表观遗传重编程和重表达的重要乳腺癌相关的沉默基因编码E-钙粘蛋白，雌激素受体α和视黄酸受体β和受损的肿瘤生长在体内。有趣的是，SID诱饵在三负M中有效。D. Anderson-Metastatic Breast-231（MDA-MB-231）乳腺癌细胞系，恢复对17 β-雌二醇、他莫昔芬和类维生素A的敏感性。因此，可以阻断PAH 2和SID蛋白之间相互作用的小分子的开发为治疗这种类型的乳腺癌提供了一种靶向表观遗传方法，也可能具有更广泛的治疗意义。
Sin3A/B is a master transcriptional scaffold and corepressor that plays an essential role in the regulation of gene transcription and maintenance of chromatin structure, and its inappropriate recruitment has been associated with aberrant gene silencing in cancer. Sin3A/B are highly related, large, multidomian proteins that interact with a wide variety of transcription factors and corepressor components, and we examined whether disruption of the function of a specific domain could lead to epigenetic reprogramming and derepression of specific subsets of genes. To this end, we selected the Sin3A/B-paired amphipathic alpha-helices (PAH2) domain based on its established role in mediating the effects of a relatively small number of transcription factors containing a PAH2-binding motif known as the Sin3 interaction domain (SID). Here, we show that in both human and mouse breast cancer cells, the targeted disruption of Sin3 function by introduction of a SID decoy that interferes with PAH2 binding to SID-containing partner proteins reverted the silencing of genes involved in cell growth and differentiation. In particular, the SID decoy led to epigenetic reprogramming and reexpression of the important breast cancer-associated silenced genes encoding E-cadherin, estrogen receptor alpha, and retinoic acid receptor beta and impaired tumor growth in vivo. Interestingly, the SID decoy was effective in the triple-negative M. D. Anderson-Metastatic Breast-231 (MDA-MB-231) breast cancer cell line, restoring sensitivity to 17 beta-estradiol, tamoxifen, and retinoids. Therefore, the development of small molecules that can block interactions between PAH2 and SID-containing proteins offers a targeted epigenetic approach for treating this type of breast cancer that may also have wider therapeutic implications.