1. Epigenetic control of melanoma cell invasiveness by the stem cell factor SALL4.
- Author
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Diener J, Baggiolini A, Pernebrink M, Dalcher D, Lerra L, Cheng PF, Varum S, Häusel J, Stierli S, Treier M, Studer L, Basler K, Levesque MP, Dummer R, Santoro R, Cantù C, and Sommer L
- Subjects
- Acetylation, Animals, Base Sequence, Carcinogenesis genetics, Carcinogenesis pathology, Cell Adhesion genetics, Cell Line, Tumor, Cell Lineage, Cell Proliferation, DNA-Binding Proteins metabolism, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Histone Deacetylase 2 metabolism, Histones metabolism, Humans, Melanocytes metabolism, Melanocytes pathology, Mice, Nude, Mice, Transgenic, Neoplasm Invasiveness, Neoplasm Micrometastasis, Protein Binding, Tumor Burden, Mice, Epigenesis, Genetic, Melanoma genetics, Melanoma pathology, Skin Neoplasms genetics, Skin Neoplasms pathology, Stem Cell Factor metabolism, Transcription Factors metabolism
- 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::Nras
Q61K ; 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., (© 2021. The Author(s).)- Published
- 2021
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