Abstract

The microphthalmia associated transcription factor (MITF) is a critical regulator of melanocyte development and differentiation. It also plays an important role in melanoma where it has been described as a molecular rheostat that, depending on activity levels, allows reversible switching between different cellular states. Here we show that MITF directly represses the expression of genes associated with the extracellular matrix (ECM) and focal adhesion pathways in human melanoma cells as well as of regulators of epithelial to mesenchymal transition (EMT) such as CDH2, thus affecting cell morphology and cell-matrix interactions. Importantly, we show that these effects of MITF are reversible, as expected from the rheostat model. The number of focal adhesion points increased upon MITF knockdown, a feature observed in drug resistant melanomas. Cells lacking MITF are similar to the cells of minimal residual disease observed in both human and zebrafish melanomas. Our results suggest that MITF plays a critical role as a repressor of gene expression and is actively involved in shaping the microenvironment of melanoma cells in a cell-autonomous manner.

Data availability

MITF CUT&RUN sequencing data have been deposited in GEO under accession codes GSE153020 and the RNA-Seq data discussed in this publication are available under the accession number GSE163646.

The following previously published data sets were used

Article and author information

Author details

  1. Ramile Dilshat

    Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2126-2902
  2. Valerie Fock

    Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
    Competing interests
    The authors declare that no competing interests exist.
  3. Colin Kenny

    Department of Anatomy and Cell biology, Carver College of Medicine, University of Iowa, Iowa, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ilse   Gerritsen

    Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
    Competing interests
    The authors declare that no competing interests exist.
  5. Romain Maurice Jacques Lasseur

    Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
    Competing interests
    The authors declare that no competing interests exist.
  6. Jana Travnickova 

    MRC Institute of Genetics and Molecular Medicine, MRC Human Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Ossia Margarita Eichhoff 

    Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3319-1312
  8. Philipp Cerny

    Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
    Competing interests
    The authors declare that no competing interests exist.
  9. Katrin Möller

    Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
    Competing interests
    The authors declare that no competing interests exist.
  10. Sara Sigurbjörnsdóttir 

    Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
    Competing interests
    The authors declare that no competing interests exist.
  11. Kritika Kirty

    Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
    Competing interests
    The authors declare that no competing interests exist.
  12. Berglind Ósk Einarsdottir

    Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
    Competing interests
    The authors declare that no competing interests exist.
  13. Phil F Cheng

    Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2940-006X
  14. Mitchell Levesque

    Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  15. Robert A Cornell

    College of Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4207-9100
  16. E Elizabeth Patton

    MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2570-0834
  17. Lionel Larue

    Institut Curie, Orsay, France
    Competing interests
    The authors declare that no competing interests exist.
  18. Marie de Tayrac 

    CNRS, IGDR (Institut de Génétique et Développement de Rennes)-UMR 6290, F-35000, Univ Rennes1, Rennes, France
    Competing interests
    The authors declare that no competing interests exist.
  19. Erna Magnúsdóttir 

    Department of Anatomy, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3369-4390
  20. Margrét Helga Ögmundsdóttir

    Department of Biochemistry and Molecular Biology, University of Iceland, Reykjavik, Iceland
    Competing interests
    The authors declare that no competing interests exist.
  21. Eirikur Steingrimsson

    Department of Biochemistry, University of Iceland, Reykjavik, Iceland
    For correspondence
    eirikurs@hi.is
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5826-7486

Funding

Icelandic Centre for Research (184861 and 767 207067)

  • Eirikur Steingrimsson

National Institutes of Health (A2062457)

  • Robert A Cornell

H2020 European Research Council (ZF-MEL-CHEMBIO-648489)

  • E Elizabeth Patton

L'Oreal Melanoma Research Alliance (401181)

  • E Elizabeth Patton

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. C Daniela Robles-Espinoza, International Laboratory for Human Genome Research, Mexico

Version history

  1. Received: September 14, 2020
  2. Accepted: January 11, 2021
  3. Accepted Manuscript published: January 13, 2021 (version 1)
  4. Version of Record published: February 3, 2021 (version 2)

Copyright

© 2021, Dilshat et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ramile Dilshat
  2. Valerie Fock
  3. Colin Kenny
  4. Ilse   Gerritsen
  5. Romain Maurice Jacques Lasseur
  6. Jana Travnickova 
  7. Ossia Margarita Eichhoff 
  8. Philipp Cerny
  9. Katrin Möller
  10. Sara Sigurbjörnsdóttir 
  11. Kritika Kirty
  12. Berglind Ósk Einarsdottir
  13. Phil F Cheng
  14. Mitchell Levesque
  15. Robert A Cornell
  16. E Elizabeth Patton
  17. Lionel Larue
  18. Marie de Tayrac 
  19. Erna Magnúsdóttir 
  20. Margrét Helga Ögmundsdóttir
  21. Eirikur Steingrimsson
(2021)
MITF reprograms the extracellular matrix and focal adhesion in melanoma
eLife 10:e63093.
https://doi.org/10.7554/eLife.63093

Share this article

https://doi.org/10.7554/eLife.63093

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