Identification of a ZEB2-MITF-ZEB1 transcriptional network that controls melanogenesis and melanoma progression

被引:164
作者
Denecker, G. [1 ,2 ]
Vandamme, N. [1 ,2 ]
Akay, O. [1 ,2 ]
Koludrovic, D. [3 ]
Taminau, J. [1 ,2 ]
Lemeire, K. [2 ]
Gheldof, A. [1 ,2 ]
De Craene, B. [1 ,2 ]
Van Gele, M. [4 ]
Brochez, L. [4 ]
Udupi, G. M. [5 ,6 ]
Rafferty, M. [6 ]
Balint, B. [6 ]
Gallagher, W. M. [6 ]
Ghanem, G. [7 ]
Huylebroeck, D. [8 ,9 ]
Haigh, J. [2 ,10 ]
van den Oord, J. [11 ]
Larue, L. [12 ]
Davidson, I. [3 ]
Marine, J-C [13 ,14 ]
Berx, G. [1 ,2 ]
机构
[1] VIB, Inflammat Res Ctr, Unit Mol & Cellular Oncol, B-9052 Ghent, Zwijnaarde, Belgium
[2] Univ Ghent, Dept Biomed Mol Biol, B-9052 Ghent, Belgium
[3] Univ Strasbourg, INSERM, CNRS, Inst Genet & Biol Mol & Cellulaire, Illkirch Graffenstaden, France
[4] Ghent Univ Hosp, Dept Dermatol, B-9000 Ghent, Belgium
[5] Univ Coll Dublin, UCD Conway Inst, UCD Sch Biomol & Biomed Sci, Dublin 4, Ireland
[6] Univ Coll Dublin, OncoMark Ltd, Nova UCD, Dublin 4, Ireland
[7] Inst Jules Bordet, B-1000 Brussels, Belgium
[8] Katholieke Univ Leuven, Dept Dev & Regenerat, Lab Mol Biol Celgen, B-3000 Leuven, Belgium
[9] Erasmus MC, Dept Cell Biol, NL-3015 GE Rotterdam, Netherlands
[10] VIB, Dept Mol Biomed Res, Vasc Cell Biol Unit, Ghent, Belgium
[11] Katholieke Univ Leuven, Univ Hosp Leuven, Dept Pathol, Leuven, Belgium
[12] Inst Curie, CNRS, INSERM, U1021, F-91405 Orsay, France
[13] VIB, Ctr Biol Dis, Lab Mol Canc Biol, Leuven, Belgium
[14] Katholieke Univ Leuven, Ctr Human Genet, Leuven, Belgium
关键词
STEM-CELL MAINTENANCE; TUMOR PROGRESSION; EXPRESSION; GENE; HAIR; EMT; MELANOBLASTS; INHIBITION; MECHANISMS; DELETION;
D O I
10.1038/cdd.2014.44
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1250 / 1261
页数:12
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