Epigenetic control of melanoma cell invasiveness by the stem cell factor SALL4

Johanna Diener, Arianna Baggiolini, Mattias Pernebrink, Damian Dalcher, Luigi Lerra, Phil F. Cheng, Sandra Varum, Jessica Häusel, Salome Stierli, Mathias Treier, Lorenz Studer, Konrad Basler, Mitchell P. Levesque, Reinhard Dummer, Raffaella Santoro, Claudio Cantù and Lukas Sommer ()
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Johanna Diener: University of Zürich, Institute of Anatomy
Arianna Baggiolini: University of Zürich, Institute of Anatomy
Mattias Pernebrink: Linköping University
Damian Dalcher: University of Zürich, Department of Molecular Mechanisms of Disease
Luigi Lerra: University of Zürich, Department of Molecular Mechanisms of Disease
Phil F. Cheng: University Hospital of Zürich, Department of Dermatology
Sandra Varum: University of Zürich, Institute of Anatomy
Jessica Häusel: University of Zürich, Institute of Anatomy
Salome Stierli: University of Zürich, Institute of Anatomy
Mathias Treier: Max-Delbrück-Center for Molecular Medicine
Lorenz Studer: Memorial Sloan Kettering Cancer Center
Konrad Basler: University of Zürich, Institute of Molecular Life Sciences
Mitchell P. Levesque: University Hospital of Zürich, Department of Dermatology
Reinhard Dummer: University Hospital of Zürich, Department of Dermatology
Raffaella Santoro: University of Zürich, Department of Molecular Mechanisms of Disease
Claudio Cantù: Linköping University
Lukas Sommer: University of Zürich, Institute of Anatomy

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Melanoma cells rely on developmental programs during tumor initiation and progression. Here we show that the embryonic stem cell (ESC) factor Sall4 is re-expressed in the Tyr::NrasQ61K; Cdkn2a−/− melanoma model and that its expression is necessary for primary melanoma formation. Surprisingly, while Sall4 loss prevents tumor formation, it promotes micrometastases to distant organs in this melanoma-prone mouse model. Transcriptional profiling and in vitro assays using human melanoma cells demonstrate that SALL4 loss induces a phenotype switch and the acquisition of an invasive phenotype. We show that SALL4 negatively regulates invasiveness through interaction with the histone deacetylase (HDAC) 2 and direct co-binding to a set of invasiveness genes. Consequently, SALL4 knock down, as well as HDAC inhibition, promote the expression of an invasive signature, while inhibition of histone acetylation partially reverts the invasiveness program induced by SALL4 loss. Thus, SALL4 appears to regulate phenotype switching in melanoma through an HDAC2-mediated mechanism.

Date: 2021
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DOI: 10.1038/s41467-021-25326-8

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