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In melanoma, a phenotype switch from proliferation to invasion underpins metastasis, the major cause of melanoma-associated death. The transition from radial to vertical growth phase (invasive) melanoma is characterized by downregulation of both E-cadherin (CDH1) and MITF and upregulation of the key cancer-associated gene TBX3 and the phosphatidylinositol 3 kinase signaling pathway. Yet, whether and how these diverse events are linked remains poorly understood. Here, we show that TBX3 directly promotes expression of ID1, a dominant-negative regulator of basic helix-loop-helix transcription factors, and that ID1 decreases MITF binding and upregulation of CDH1. Significantly, we show that TBX3 activation of ID1 is necessary for TBX3 to enhance melanoma cell migration, and the mechanistic links between TBX3, ID1, MITF, and invasion revealed here are reflected in their expression in human melanomas. Our results reveal that melanoma migration is promoted through a TBX3-ID1-MITF-E-cadherin axis and that ID1-mediated repression of MITF activity may reinforce maintenance of an MITFLow phenotype associated with disease progression and therapy resistance.

Original publication




Journal article


The Journal of investigative dermatology

Publication Date





2250 - 2260.e2


Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.


Cell Line, Tumor, Humans, Melanoma, Skin Neoplasms, T-Box Domain Proteins, Cadherins, Signal Transduction, Cell Movement, Gene Expression Regulation, Neoplastic, Microphthalmia-Associated Transcription Factor, Inhibitor of Differentiation Protein 1, Transcriptional Activation, Carcinogenesis