CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China.
State Key Laboratory of Oncology in Southern China and Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China.
Nat Commun. 2017 May 5;8:15278. doi: 10.1038/ncomms15278.
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 both in vitro and in 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.
Menin 是一种神秘的蛋白质，具有独特的能力，可以在依赖于上下文的情况下抑制或促进肿瘤发生。Menin 促进致癌功能的作用主要归因于其在形成 MLL 甲基转移酶复合物中的重要作用，该复合物介导 H3K4me3。在这里，我们发现 Menin 在一种不依赖于 H3K4me3 活性的方式下增强致癌基因 MYC 的转录活性的意外作用。有趣的是，我们发现 Menin 与 MYC 的 TAD 结构域直接相互作用，并与 MYC 共定位到 E-Box 以依赖于 P-TEFb 的方式增强 MYC 靶基因的转录。我们进一步证明，通过在癌细胞中转录促进 MYC 靶基因的表达，Menin 刺激细胞增殖和细胞代谢，无论是在体外还是体内。我们的结果揭示了 Menin 作为致癌调节因子的一种先前未被认识的机制，这对于 MYC 介导的基因转录至关重要。
