Deletion of the proline-rich region of the murine metastasis susceptibility gene Brd4 promotes epithelial-to-mesenchymal transition- and stem cell-like conversion.
Deletion of the proline-rich region of the murine metastasis susceptibility gene Brd4 promotes epithelial-to-mesenchymal transition- and stem cell-like conversion.
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DOI：
10.1158/0008-5472.can-10-4417
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发表时间：
2011-04-15
期刊：
影响因子：
11.2
通讯作者：
Hunter KW
中科院分区：
文献类型：
--
作者：
Alsarraj J;Walker RC;Webster JD;Geiger TR;Crawford NP;Simpson RM;Ozato K;Hunter KW
含溴结构域的染色质修饰因子BRD4是乳腺癌进展和转移的遗传易感基因，但其在这些环境中的功能尚未被探索。在这里，我们表明，删除BRD4的任何一个溴结构域对BRD4的转移抑制能力影响不大。相反，在SEED结构域后截断BRD4的天然短异构体的表达恢复了进展和转移能力。出乎意料的是，富含脯氨酸的区域的缺失诱导了间充质样转化和获得癌症干细胞样特性，这是由羧基末端P-TEFb结合域介导的。这个富含脯氨酸的区域的缺失也诱导了一个基因表达标记，该标记预测了人类乳腺癌数据集和重叠的G3级人类乳腺肿瘤的不良预后。因此，我们的研究结果表明，BRD4可能会改变肿瘤的易感性，使其在转移过程中转变为更加去分化或原始状态。
The bromodomain-containing chromatin modifying factor BRD4 is an inherited susceptibility gene for breast cancer progression and metastasis, but its functionality in these settings has yet to be explored. Here we show that deletion of either of the BRD4 bromodomains had modest effects on the metastatic suppression ability of BRD4. In contrast, expression of the natural short isoform of BRD4 that truncates the protein after the SEED domain restored progression and metastatic capacity. Unexpectedly, deletion of the proline-rich region induced mesenchymal-like conversion and acquisition of cancer stem cell-like properties, which are mediated by the carboxy terminal P-TEFb binding domain. Deletion of this proline-rich region also induced a gene expression signature that predicted poor outcome in human breast cancer datasets and that overlapped G3 grade human breast tumors. Thus, our findings suggest that BRD4 may be altering the predisposition of tumors to undergo conversion to a more-de-differentiated or primitive state during metastatic progression.