Menin enhances c-Myc-mediated transcription to promote cancer progression.
Menin enhances c-Myc-mediated transcription to promote cancer progression.
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Menin 增强 c-Myc 介导的转录以促进癌症进展
DOI：
10.1038/ncomms15278
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发表时间：
2017-05-05
影响因子：
16.6
通讯作者：
Gao P
中科院分区：
文献类型：
--
作者：
Wu G;Yuan M;Shen S;Ma X;Fang J;Zhu L;Sun L;Liu Z;He X;Huang D;Li T;Li C;Wu J;Hu X;Li Z;Song L;Qu K;Zhang H;Gao P
Menin是一种神秘的蛋白质，它以一种上下文依赖的方式显示出抑制或促进肿瘤发生的独特能力。Menin促进致癌功能的作用在很大程度上归因于它在形成MLL甲基转移酶复合体方面的重要作用，MLL甲基转移酶复合体介导H3K4me3。在这里，我们发现了一个意想不到的作用，即通过一种独立于H3K4me3活性的方式增强癌基因myc的反式活性。有趣的是，我们发现Menin直接与MYC的TAD结构域相互作用，并与MYC共定位到E-Box，以P-TEFb依赖的方式增强MYC靶基因的转录。我们进一步证明，通过在转录上促进癌细胞中MYC靶基因的表达，Menin在体外和体内都能刺激细胞增殖和细胞代谢。我们的结果揭示了一个以前未被认识的机制，通过该机制，Menin作为致癌调节因子发挥作用，这对MYC介导的基因转录至关重要。
Menin is an enigmatic protein that displays unique ability to either suppress or promote tumorigenesis in a context-dependent manner. The role for Menin to promote oncogenic functions has been largely attributed to its essential role in forming the MLL methyltransferase complex, which mediates H3K4me3. Here, we identify an unexpected role of Menin in enhancing the transactivity of oncogene MYC in a way independent of H3K4me3 activity. Intriguingly, we find that Menin interacts directly with the TAD domain of MYC and co-localizes with MYC to E-Box to enhance the transcription of MYC target genes in a P-TEFb-dependent manner. We further demonstrate that, by transcriptionally promoting the expression of MYC target genes in cancer cells, Menin stimulates cell proliferation and cellular metabolism bothin vitroandin vivo. Our results uncover a previously unappreciated mechanism by which Menin functions as an oncogenic regulatory factor that is critical for MYC-mediated gene transcription.