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

Oncogene volume 40, pages 1091–1105 (2021)Cite this article

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Abstract

Metastatic melanoma is hallmarked by its ability of phenotype switching to more slowly proliferating, but highly invasive cells. Here, we tested the impact of signal transducer and activator of transcription 3 (STAT3) on melanoma progression in association with melanocyte inducing transcription factor (MITF) expression levels. We established a mouse melanoma model for deleting Stat3 in melanocytes with specific expression of human hyperactive NRASQ61K in an Ink4a-deficient background, two frequent driver mutations in human melanoma. Mice devoid of Stat3 showed early disease onset with higher proliferation in primary tumors, but displayed significantly diminished lung, brain, and liver metastases. Whole-genome expression profiling of tumor-derived cells also showed a reduced invasion phenotype, which was further corroborated by 3D melanoma model analysis. Notably, loss or knockdown of STAT3 in mouse or human cells resulted in the upregulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3-induced CAAT Box Enhancer Binding Protein (CEBP) expression was sufficient to suppress MITF transcription. Epigenetic analysis by ATAC-seq confirmed that CEBPa/b binding to the MITF enhancer region silenced the MITF locus. Finally, by classification of patient-derived melanoma samples, we show that STAT3 and MITF act antagonistically and hence contribute differentially to melanoma progression. We conclude that STAT3 is a driver of the metastatic process in melanoma and able to antagonize MITF via direct induction of CEBP family member transcription.

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Fig. 1: STAT3 knockout in melanoma induced earlier tumor onset, but reduced metastasis.
Fig. 2: Loss of Stat3-induced MITF pathway in melanoma cells.
Fig. 3: Transcriptome analysis and functional testing revealed abrogated invasion and increased proliferation after STAT3 knockout.
Fig. 4: Expression of receptor tyrosine kinases displays a YIN/YANG dualism corresponding to STAT3/MITF interplay.
Fig. 5: MITF expression depends on the STAT3 target Cebpa and Cebpb.
Fig. 6: Human melanoma cells induce MITF and proliferation upon loss of STAT3.
Fig. 7: Human patients with STAT3low, CEBPAlow, CEBPBlow, and MITFhigh signature show worsened clinical outcome.

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Acknowledgements

We thank Safia Zahma, Birgit Schütz, Eva Bauer, Michaela Schlederer, and Karin Neumüller for excellent technical assistance. We also thank the Biomedical Sequencing Facility at CeMM for assistance with next-generation sequencing. VP was supported by the grant AIRC IG16930, AS, OE, RZ, and RM were supported by a private melanoma research donation from Liechtenstein, RM was further supported by two network grants SFB-F061 and SFB-F047, and RS, KK, MV, and MM were supported by P 25336-B13, all from the Austrian Science Fund (FWF).

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  1. These authors contributed equally: Alexander Swoboda, Robert Soukup

Authors and Affiliations

  1. Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria

    Alexander Swoboda, Bettina Wingelhofer, Ha T. T. Pham, Jaqueline Horvath, Dagmar Stoiber, Lukas Kenner & Richard Moriggl

  2. Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria

    Alexander Swoboda, Oliver Eckel, Bettina Wingelhofer, Ha T. T. Pham & Richard Moriggl

  3. Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria

    Robert Soukup, Oliver Eckel, Katharina Kinslechner, David Schörghofer, Maria Vallianou, Boris Kovacic, Markus Hengstschläger & Mario Mikula

  4. Department of Biosciences, Cancer Cluster Salzburg, University of Salzburg, Salzburg, Austria

    Christina Sternberg & Fritz Aberger

  5. Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

    Jaqueline Horvath & Dagmar Stoiber

  6. Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria

    Lukas Kenner

  7. Unit of Pathology of Laboratory Animals, University of Veterinary Medicine, Vienna, Austria

    Lukas Kenner

  8. CBMed Core Lab2, Medical University of Vienna, Vienna, Austria

    Lukas Kenner

  9. Institute Curie, Normal and Pathological Development of Melanocytes, CNRS UMR3347, INSERM U1021 Equipe labellisée, Orsay, France

    Lionel Larue

  10. Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy

    Valeria Poli

  11. ISREC, Swiss Federal Institute of Technology in Lausanne, Lausanne, Switzerland

    Friedrich Beermann

  12. Department of Stem Cell Biology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan

    Takashi Yokota

  13. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    Stefan Kubicek, Thomas Krausgruber, André F. Rendeiro & Christoph Bock

  14. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria

    Christoph Bock

  15. Max Planck Institute for Informatics, Saarland Informatics Campus, Saarbrücken, Germany

    Christoph Bock

  16. Institute of Cancer Research, Medical University of Vienna, Vienna, Austria

    Rainer Zenz

  17. Department of Dermatology, Skin and Endothelium Research Division (SERD), Medical University of Vienna, Vienna, Austria

    Peter Petzelbauer

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  1. Alexander Swoboda
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Swoboda, A., Soukup, R., Eckel, O. et al. STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pathway. Oncogene 40, 1091–1105 (2021). https://doi.org/10.1038/s41388-020-01584-6

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