Breast cancer-associated fibroblasts confer AKT1-mediated epigenetic silencing of Cystatin M in epithelial cells.
Breast cancer-associated fibroblasts confer AKT1-mediated epigenetic silencing of Cystatin M in epithelial cells.
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DOI：
10.1158/0008-5472.can-08-0288
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发表时间：
2008-12-15
期刊：
影响因子：
11.2
通讯作者：
Huang TH
中科院分区：
文献类型：
--
作者：
Lin HJ;Zuo T;Lin CH;Kuo CT;Liyanarachchi S;Sun S;Shen R;Deatherage DE;Potter D;Asamoto L;Lin S;Yan PS;Cheng AL;Ostrowski MC;Huang TH
组蛋白修饰和启动子超甲基化之间的相互作用为癌症中的表观遗传基因沉默提供了一个原因解释。对指导这一过程的上游引发剂知之甚少。在这里，我们报告说，胱抑素M（CST6）肿瘤抑制基因是同时下调与其他位点的乳腺上皮细胞与癌症相关的成纤维细胞（CAFs）共培养。CST6的启动子超甲基化与上皮细胞中AKT1的异常激活以及CAF抑制导致的INNP4B调节因子的失能相关。在启动子处建立由三甲基-H3K27和二甲基-H3K9标记的抑制性染色质和从头DNA甲基化。研究结果表明，微环境刺激是这种表观遗传级联反应的触发因素，导致乳腺肿瘤中CST6的长期沉默。我们目前的研究结果暗示了一种因果机制，它定义了肿瘤间质成纤维细胞如何通过操纵乳腺上皮细胞的表观基因组来支持肿瘤进展。该结果还强调了上皮细胞和周围成纤维细胞之间直接细胞-细胞接触的重要性，这种接触赋予了这种表观遗传扰动。由于这种双向相互作用是预期的，所描述的共培养系统可用于确定上皮细胞因子对成纤维细胞在未来的研究中的影响。
The interplay between histone modifications and promoter hypermethylation provides a causative explanation for epigenetic gene silencing in cancer. Less is known about the upstream initiators that direct this process. Here, we report that the Cystatin M (CST6) tumor suppressor gene is concurrently down-regulated with other loci in breast epithelial cells co-cultured with cancer-associated fibroblasts (CAFs). Promoter hypermethylation of CST6 is associated with aberrant AKT1 activation in epithelial cells, as well as the disabled INNP4B regulator resulted from the suppression by CAFs. Repressive chromatin, marked by trimethyl-H3K27 and dimethyl-H3K9, and de novo DNA methylation is established at the promoter. The findings suggest that microenvironmental stimuli are triggers in this epigenetic cascade, leading to the long-term silencing of CST6 in breast tumors. Our present findings implicate a causal mechanism defining how tumor stromal fibroblasts support neoplastic progression by manipulating the epigenome of mammary epithelial cells. The result also highlights the importance of direct cell-cell contract between epithelial cells and the surrounding fibroblasts that confer this epigenetic perturbation. Since this two-way interaction is anticipated, the described co-culture system can be used to determine the effect of epithelial factors on fibroblasts in future studies.