Denecker G, Vandamme N, Akay O, Koludrovic D, Taminau J, Lemeire K, Gheldof A, De Craene B, Van Gele M, Brochez L, Udupi G M, Rafferty M, Balint B, Gallagher W M, Ghanem G, Huylebroeck D, Haigh J, van den Oord J, Larue L, Davidson I, Marine J-C, Berx G
1] Unit of Molecular and Cellular Oncology, Inflammation Research Center, VIB, 9052 Ghent, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université de Strasbourg, Illkirch, France.
Cell Death Differ. 2014 Aug;21(8):1250-61. doi: 10.1038/cdd.2014.44. Epub 2014 Apr 25.
Deregulation of signaling pathways that control differentiation, expansion and migration of neural crest-derived melanoblasts during normal development contributes also to melanoma progression and metastasis. Although several epithelial-to-mesenchymal (EMT) transcription factors, such as zinc finger E-box binding protein 1 (ZEB1) and ZEB2, have been implicated in neural crest cell biology, little is known about their role in melanocyte homeostasis and melanoma. Here we show that mice lacking Zeb2 in the melanocyte lineage exhibit a melanoblast migration defect and, unexpectedly, a severe melanocyte differentiation defect. Loss of Zeb2 in the melanocyte lineage results in a downregulation of the Microphthalmia-associated transcription factor (Mitf) and melanocyte differentiation markers concomitant with an upregulation of Zeb1. We identify a transcriptional signaling network in which the EMT transcription factor ZEB2 regulates MITF levels to control melanocyte differentiation. Moreover, our data are also relevant for human melanomagenesis as loss of ZEB2 expression is associated with reduced patient survival.
在正常发育过程中，控制神经嵴衍生的黑素母细胞分化、增殖和迁移的信号通路失调也会导致黑色素瘤的进展和转移。尽管一些上皮-间质转化（EMT）转录因子，如锌指E盒结合蛋白1（ZEB1）和ZEB2，已被证明与神经嵴细胞生物学有关，但它们在黑素细胞稳态和黑色素瘤中的作用仍知之甚少。在这里，我们表明黑素细胞谱系中缺乏Zeb2的小鼠表现出黑素母细胞迁移缺陷，并且出乎意料的是，还表现出严重的黑素细胞分化缺陷。黑素细胞谱系中Zeb2的缺失导致小眼相关转录因子（Mitf）和黑素细胞分化标志物的下调，同时伴随着Zeb1的上调。我们确定了一个转录信号网络，其中EMT转录因子ZEB2调节MITF水平以控制黑素细胞分化。此外，我们的数据对于人类黑色素瘤的发生也具有相关性，因为ZEB2表达的缺失与患者生存率降低有关。
