MITF reprograms the extracellular matrix and focal adhesion in melanoma

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 dif...

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Published in:	eLife Vol. 10
Main Authors:	Dilshat, Ramile, Fock, Valerie, Kenny, Colin, Gerritsen, Ilse, Lasseur, Romain Maurice Jacques, Travnickova, Jana, Eichhoff, Ossia M, Cerny, Philipp, Möller, Katrin, Sigurbjörnsdóttir, Sara, Kirty, Kritika, Einarsdottir, Berglind Ósk, Cheng, Phil F, Levesque, Mitchell, Cornell, Robert A, Patton, E Elizabeth, Larue, Lionel, de Tayrac, Marie, Magnúsdóttir, Erna, Ögmundsdóttir, Margrét Helga, Steingrimsson, Eirikur
Format:	Journal Article
Language:	English
Published:	England eLife Science Publications, Ltd 13-01-2021 eLife Sciences Publications Ltd eLife Sciences Publication eLife Sciences Publications, Ltd
Subjects:	Adhesion Cancer Biology Cell Line, Tumor CRISPR Cytology Drug resistance Epithelial-Mesenchymal Transition Extracellular matrix Extracellular Matrix - metabolism focal adhesion Focal Adhesions - metabolism Gene expression Genetic aspects Genetics and Genomics Genotype & phenotype Humans Kinases Life Sciences Medical prognosis Melanoma Melanoma - metabolism Mesenchyme Metastasis Microenvironments Microphthalmia-associated transcription factor Microphthalmia-Associated Transcription Factor - genetics Microphthalmia-Associated Transcription Factor - metabolism Minimal residual disease MITF Mutation Proteins repression Skin cancer Tumors focal adhesion genetics genomics melanoma MITF cancer biology repression human extracellular matrix
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
ISSN:	2050-084X 2050-084X
DOI:	10.7554/eLife.63093