Contribution of polycomb homologues Bmi-1 and Mel-18 to medulloblastoma pathogenesis
Contribution of polycomb homologues Bmi-1 and Mel-18 to medulloblastoma pathogenesis
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DOI：
10.1128/mcb.02244-06
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发表时间：
2007-07-01
影响因子：
5.3
通讯作者：
Benson, John D.
中科院分区：
文献类型：
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作者：
Wiederschain, Dmitri;Chen, Lin;Benson, John D.
Bmi-1和Mel-18是属于Polycomb转录调节子组的结构同源物，并且被认为通过改变特定启动子处的染色质状态来稳定地维持基因表达的抑制。虽然许多临床和实验观察表明Bmi-1与人类肿瘤发生有关，但尚未研究Mel-18在癌细胞生长中的作用。我们在这里报告，短发夹RNA介导的敲低人髓母细胞瘤DAOY细胞中的Bmi-1或Mel-18导致增殖抑制、克隆形成存活率丧失、锚定非依赖性生长和裸鼠肿瘤形成抑制。此外，Bmi-1和Mel-18两者的过表达显著增加Rat 1成纤维细胞的克隆形成存活。相反，Bmi-1或Mel-18单独稳定下调不影响正常人WI 38成纤维细胞的生长。从癌细胞中分离的Bmi-1和Mel-18蛋白复合物的基于蛋白质组学的表征揭示了它们各自组成的实质相似性。最后，基因表达分析确定了许多可能由Bmi-1和Mel-18控制的癌症相关途径，并且还表明这些Polycomb蛋白调节一组常见的基因靶点。综上所述，这些结果表明Bmi-1和Mel-18在癌细胞生长中可能具有重叠的功能。
Bmi-1 and Mel-18 are structural homologues that belong to the Polycomb group of transcriptional regulators and are believed to stably maintain repression of gene expression by altering the state of chromatin at specific promoters. While a number of clinical and experimental observations have implicated Bmi-1 in human tumorigenesis, the role of Mel-18 in cancer cell growth has not been investigated. We report here that short hairpin RNA-mediated knockdown of either Bmi-1 or Mel-18 in human medulloblastoma DAOY cells results in the inhibition of proliferation, loss of clonogenic survival, anchorage-independent growth, and suppression of tumor formation in nude mice. Furthermore, overexpression of both Bmi-1 and Mel-18 significantly increases the clonogenic survival of Rat1 fibroblasts. In contrast, stable downregulation of Bmi-1 or Mel-18 alone does not affect the growth of normal human WI38 fibroblasts. Proteomics-based characterization of Bmi-1 and Mel-18 protein complexes isolated from cancer cells revealed substantial similarities in their respective compositions. Finally, gene expression analysis identified a number of cancer-relevant pathways that may be controlled by Bmi-1 and Mel-18 and also showed that these Polycomb proteins regulate a set of common gene targets. Taken together, these results suggest that Bmi-1 and Mel-18 may have overlapping functions in cancer cell growth.