Identification of a ZEB2-MITF-ZEB1 transcriptional network that controls melanogenesis and melanoma progression.
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.
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.
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Denecker
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.
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Vandamme
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.
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O
Akay
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université de Strasbourg, Illkirch, France.
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Koludrovic
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.
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Taminau
Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
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Lemeire
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.
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Gheldof
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.
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De Craene
Department of Dermatology, Ghent University Hospital, 9000 Ghent, Belgium.
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Van Gele
Department of Dermatology, Ghent University Hospital, 9000 Ghent, Belgium.
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Brochez
1] UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College, Dublin 4, Ireland [2] OncoMark Limited, Nova UCD, Belfield Innovation Park, University College Dublin, Belfield, Dublin 4, Ireland.
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Udupi
OncoMark Limited, Nova UCD, Belfield Innovation Park, University College Dublin, Belfield, Dublin 4, Ireland.
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M
Rafferty
OncoMark Limited, Nova UCD, Belfield Innovation Park, University College Dublin, Belfield, Dublin 4, Ireland.
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B
Balint
1] UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College, Dublin 4, Ireland [2] OncoMark Limited, Nova UCD, Belfield Innovation Park, University College Dublin, Belfield, Dublin 4, Ireland.
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Gallagher
Institute Jules Bordet, Brussels, Belgium.
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Ghanem
1] Laboratory of Molecular Biology (Celgen), Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium [2] Department of Cell Biology, Erasmus MC, 3015 GE Rotterdam, The Netherlands.
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Huylebroeck
1] Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium [2] Vascular Cell Biology Unit, Department for Molecular Biomedical Research, VIB, Ghent, Belgium.
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J
Haigh
Department of Pathology, University Hospital Leuven, KU Leuven, Leuven, Belgium.
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van den Oord
Curie Institute, Developmental Genetics of Melanocytes, Centre National de la Recherche Scientifique (CNRS) UMR3347, Institut National de la Santé et de la Recherche Médicale (INSERM) U1021, Orsay, France.
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Larue
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université de Strasbourg, Illkirch, France.
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I
Davidson
1] Center for the Biology of Disease, Laboratory for Molecular Cancer Biology, VIB, Leuven, Belgium [2] Center for Human Genetics, KU Leuven, Leuven, Belgium.
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JC
Marine
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.
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Berx
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008544:Melanocytes / Q000166:cytology* / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; C519422:ZEB1 protein, mouse; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1