MEIS2 is essential for neuroblastoma cell survival and proliferation by transcriptional control of M-phase progression.
MEIS2 is essential for neuroblastoma cell survival and proliferation by transcriptional control of M-phase progression.
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MEIS2 通过 M 期进展的转录控制对于神经母细胞瘤细胞的存活和增殖至关重要
DOI：
10.1038/cddis.2014.370
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发表时间：
2014-09-11
影响因子：
9
通讯作者：
Ding HF
中科院分区：
文献类型：
--
作者：
Zha Y;Xia Y;Ding J;Choi JH;Yang L;Dong Z;Yan C;Huang S;Ding HF
MEIS 2在发育和器官发生中具有重要作用，并且与人类癌症的发病机制有关。MEIS 2在肿瘤发生中作用的分子基础尚不清楚。在这里，我们发现MEIS 2在人神经母细胞瘤细胞系中高度表达，并且是神经母细胞瘤细胞存活和增殖所必需的。MEIS 2在神经母细胞瘤细胞中的耗尽导致M期停滞和有丝分裂灾难，而MEIS 2的异位表达显著增强神经母细胞瘤细胞增殖、非贴壁依赖性生长和致瘤性。基因表达谱揭示了MEIS 2在维持大量晚期细胞周期基因表达中的重要作用，包括DNA复制、G2-M检查点控制和M期进展所需的基因。重要的是，我们确定MEIS 2作为MuvB-BMYB-FOXM 1复合物的转录激活因子，该复合物作为细胞周期基因表达的主调节因子发挥作用。此外，我们发现FOXM 1是MEIS 2的直接靶基因，并且是MEIS 2上调有丝分裂基因所必需的。这些发现将发育重要基因与细胞增殖的控制联系起来，并表明高MEIS 2表达是有丝分裂基因高表达的分子机制，这在预后不良的癌症中经常观察到。
MEIS2 has an important role in development and organogenesis, and is implicated in the pathogenesis of human cancer. The molecular basis of MEIS2 action in tumorigenesis is not clear. Here, we show that MEIS2 is highly expressed in human neuroblastoma cell lines and is required for neuroblastoma cell survival and proliferation. Depletion of MEIS2 in neuroblastoma cells leads to M-phase arrest and mitotic catastrophe, whereas ectopic expression of MEIS2 markedly enhances neuroblastoma cell proliferation, anchorage-independent growth, and tumorigenicity. Gene expression profiling reveals an essential role of MEIS2 in maintaining the expression of a large number of late cell-cycle genes, including those required for DNA replication, G2-M checkpoint control and M-phase progression. Importantly, we identify MEIS2 as a transcription activator of the MuvB-BMYB-FOXM1 complex that functions as a master regulator of cell-cycle gene expression. Further, we show that FOXM1 is a direct target gene of MEIS2 and is required for MEIS2 to upregulate mitotic genes. These findings link a developmentally important gene to the control of cell proliferation and suggest that high MEIS2 expression is a molecular mechanism for high expression of mitotic genes that is frequently observed in cancers of poor prognosis.