Feng Zijie, Wang Lei, Sun Yanmei, Jiang Zongzhe, Domsic John, An Chiying, Xing Bowen, Tian Jingjing, Liu Xiuheng, Metz David C, Yang Xiaolu, Marmorstein Ronen, Ma Xiaosong, Hua Xianxin
Shenzhen University College of Medicine, Medical Center and Diabetes Center, Shenzhen, China.
Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Cancer Res. 2017 Jan 15;77(2):401-411. doi: 10.1158/0008-5472.CAN-16-1567. Epub 2016 Nov 21.
Neuroendocrine tumors (NET) often harbor loss-of-function mutations in the MEN1 and DAXX tumor suppressor genes. Here, we report that the products of these genes, menin and Daxx, interact directly with each other to suppress the proliferation of NET cells, to a large degree by inhibiting expression of the membrane metallo-endopeptidase (MME). Menin and Daxx were required to enhance histone H3 lysine9 trimethylation (H3K9me3) at the MME promoter, as mediated partly by the histone H3 methyltransferase SUV39H1. Notably, the menin T429K mutation associated with a NET syndrome reduced Daxx binding, MME repression, and proliferation of NET cells. Conversely, inhibition of MME in NET cells repressed proliferation and tumor growth in vivo Our findings reveal a previously unappreciated cross-talk between two crucial tumor suppressor genes thought to work by independent pathways, focusing on MME as a common target of menin/Daxx to treat NET. Cancer Res; 77(2); 401-11. ©2016 AACR.
神经内分泌肿瘤（NET）常常在MEN1和DAXX肿瘤抑制基因中存在功能丧失性突变。在此，我们报告这些基因的产物，即Menin和Daxx，彼此直接相互作用以抑制NET细胞的增殖，很大程度上是通过抑制膜金属内肽酶（MME）的表达来实现的。Menin和Daxx对于增强MME启动子处的组蛋白H3赖氨酸9三甲基化（H3K9me3）是必需的，这部分是由组蛋白H3甲基转移酶SUV39H1介导的。值得注意的是，与一种NET综合征相关的Menin T429K突变减少了Daxx结合、MME抑制以及NET细胞的增殖。相反，在NET细胞中抑制MME可在体内抑制增殖和肿瘤生长。我们的研究结果揭示了两个被认为通过独立途径发挥作用的关键肿瘤抑制基因之间此前未被认识到的相互作用，聚焦于MME作为Menin/Daxx治疗NET的共同靶点。《癌症研究》；77(2)；401 - 411。©2016美国癌症研究协会。
