TBX3 promotes melanoma migration by transcriptional activation of ID1 which prevents activation of E-cadherin by MITF.

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 characterised by down-regulation of both E-cadherin (CDH1) and the microphthalmia-associated transcription factor (M-MITF, hereafter referred to as MITF) as well as the up-regulation of the key cancer-associated T-box transcription factor TBX3 and the PI3K signalling 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 MITFs 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.