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STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pigmentation pathway

Alexander Swoboda, Robert Soukup, Katharina Kinslechner, Bettina Wingelhofer, David Schörghofer, Christina Sternberg, Ha T. T. Pham, Maria Vallianou, Jaqueline Horvath, Dagmar Stoiber, Lukas Kenner, Lionel Larue, Valeria Poli, Friedrich Beermann, Takashi Yokota, Stefan Kubicek, Thomas Krausgruber, André F. Rendeiro, Christoph Bock, Rainer Zenz, Boris Kovacic, Fritz Aberger, Markus Hengstschläger, Peter Petzelbauer, Mario Mikula, Richard Moriggl
doi: https://doi.org/10.1101/422832
Alexander Swoboda
2Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
3Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria
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Robert Soukup
1Center for Pathobiology and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
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Katharina Kinslechner
1Center for Pathobiology and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
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Bettina Wingelhofer
2Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
3Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria
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David Schörghofer
1Center for Pathobiology and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
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Christina Sternberg
4Department of Biosciences, Cancer Cluster Salzburg, University of Salzburg, Austria
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Ha T. T. Pham
2Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
3Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria
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Maria Vallianou
1Center for Pathobiology and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
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Jaqueline Horvath
2Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
5Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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Dagmar Stoiber
2Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
5Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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Lukas Kenner
2Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
6Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria
7Unit of Pathology of Laboratory Animals, University of Veterinary Medicine, Vienna, Austria
8CBmed Corelab 2
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Lionel Larue
9Institute Curie, Normal and Pathological Development of Melanocytes, CNRS UMR3347, INSERM U1021 Equipe labellisée, Orsay, France
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Valeria Poli
10Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
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Friedrich Beermann
11ISREC, Swiss Federal Institute of Technology in Lausanne, Lausanne, Switzerland
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Takashi Yokota
12Department of Stem Cell Biology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
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Stefan Kubicek
13CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
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Thomas Krausgruber
13CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
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André F. Rendeiro
13CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
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Christoph Bock
13CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
14Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
15Max Planck Institute for Informatics, Saarland Informatics Campus, Saarbrücken, Germany
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Rainer Zenz
16Institute of Cancer Research, Medical University of Vienna, Austria
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Boris Kovacic
1Center for Pathobiology and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
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Fritz Aberger
4Department of Biosciences, Cancer Cluster Salzburg, University of Salzburg, Austria
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Markus Hengstschläger
1Center for Pathobiology and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
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Peter Petzelbauer
17Department of Dermatology, Skin and Endothelium Research Division (SERD), Medical University of Vienna, Austria
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Mario Mikula
1Center for Pathobiology and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
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  • For correspondence: richard.moriggl@vetmeduni.ac.at mario.mikula@meduniwien.ac.at
Richard Moriggl
2Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
3Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria
18Medical University of Vienna, Vienna, Austria
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  • For correspondence: richard.moriggl@vetmeduni.ac.at mario.mikula@meduniwien.ac.at
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Abstract

Metastatic melanoma is hallmarked by its ability to switch oncogenic MITF expression. Here we tested the impact of STAT3 on melanoma onset and progression in association with MITF expression levels. We established a mouse melanoma model for deleting Stat3 specifically in melanocytes with specific expression of human hyperactive NRASQ61K in an Ink4a deficient background. Mice with tissue specific Stat3 deletion showed an early onset of disease, but displayed significantly diminished lung metastases. Whole genome expression profiling also revealed a reduced invasion phenotype, which was functionally confirmed in 3D melanoma model systems. Notably, loss or knockdown of STAT3 in mouse or human cells resulted in up-regulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3 induced CEBPa/b expression was sufficient to suppress MITF transcription. Epigenetic analysis by ATAC-seq confirmed that STAT3 enabled CEBPa/b binding to the MITF enhancer region thereby silencing it. We conclude that STAT3 is a metastasis driver in melanoma able to antagonize the MITF oncogene via direct induction of CEBP family member transcription facilitating RAS-RAF-driven melanoma metastasis.

List of Abbreviations

ATAC-seq, Assay for Transposase-Accessible Chromatin using sequencing; CEBP, CAAT Box Enhancer Binding Protein; CRE, Cre recombinase; EGF, Epidermal Growth Factor; GEO, Gene Expression Omnibus; GSEA, Gene Set Enrichment Analysis; HSC70, Heat Shock 70 kDa protein; IHC, Immunohistochemistry; IL-6, Interleukin-6; JAK, Janus Kinase; MITF, Microphthalmia-Associated Transcription Factor; NSG, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice; OSM, Oncostatin M; PDGF, Platelet-Derived Growth Factor; pS, phosphoserine; pY, phosphotyrosine; RAS, Rat Sarcoma; RAF, Rapidly Accelerated Fibrosarcoma; RTK, Receptor Tyrosine Kinase; RT-PCR, Reverse Transcription Polymerase Chain Reaction; S100b, Calcium Binding Protein S100 beta; shRNA, short hairpin RNA; SOX10, Sex Determining Region Y-10; STAT, Signal Transducer and Activator of Transcription; TCGA, The Cancer Genome Atlas; TMA, Tissue Micro Array

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Posted September 20, 2018.
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STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pigmentation pathway
Alexander Swoboda, Robert Soukup, Katharina Kinslechner, Bettina Wingelhofer, David Schörghofer, Christina Sternberg, Ha T. T. Pham, Maria Vallianou, Jaqueline Horvath, Dagmar Stoiber, Lukas Kenner, Lionel Larue, Valeria Poli, Friedrich Beermann, Takashi Yokota, Stefan Kubicek, Thomas Krausgruber, André F. Rendeiro, Christoph Bock, Rainer Zenz, Boris Kovacic, Fritz Aberger, Markus Hengstschläger, Peter Petzelbauer, Mario Mikula, Richard Moriggl
bioRxiv 422832; doi: https://doi.org/10.1101/422832
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STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pigmentation pathway
Alexander Swoboda, Robert Soukup, Katharina Kinslechner, Bettina Wingelhofer, David Schörghofer, Christina Sternberg, Ha T. T. Pham, Maria Vallianou, Jaqueline Horvath, Dagmar Stoiber, Lukas Kenner, Lionel Larue, Valeria Poli, Friedrich Beermann, Takashi Yokota, Stefan Kubicek, Thomas Krausgruber, André F. Rendeiro, Christoph Bock, Rainer Zenz, Boris Kovacic, Fritz Aberger, Markus Hengstschläger, Peter Petzelbauer, Mario Mikula, Richard Moriggl
bioRxiv 422832; doi: https://doi.org/10.1101/422832

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