Abstract
Melanoma, a melanocyte-origin neoplasm, is a highly metastatic and treatment-resistance cancer. While it is well established that notch signaling activation promotes melanoma progression, little is known about the reciprocal interactions between Notch signaling and melanoma-specific pathways. Here we reveal a negative regulatory loop between Notch signaling and microphthalmia-associated transcription factor (MITF), the central regulator of melanoma progression and the driver of melanoma plasticity. We further demonstrate that Notch signaling activation, in addition to the known competition-based repression mechanism of MITF transcriptional activity, inhibits the transcription of MITF, leading to a decrease in MITF expression. We also found that MITF binds to the promoter of the gene encoding the master regulator of Notch signaling, recombination signal binding protein J kappa (RBPJK), leading to its upregulation. Our findings suggest that, once activated, Notch signaling represses MITF signaling to maintain the melanoma invasiveness and metastatic phenotype.
Highlights
Melanoma, a melanocytic neoplasm, is a highly lethal and treatment-refractory cancer [1,2,3,4] that affects an estimated 100,000 new patients worldwide each year [5]
We demonstrate that Notch signaling inhibits microphthalmia-associated transcription factor (MITF) expression, whilst MITF increases the expression of recombination signal binding protein J kappa (RBPJK)
We previously showed that Notch signaling alters the DNA binding capacity of MITF, inhibiting the transcriptional program mediated by MITF [15]
Summary
A melanocytic neoplasm, is a highly lethal and treatment-refractory cancer [1,2,3,4] that affects an estimated 100,000 new patients worldwide each year [5]. Novel approaches are required to improve this dire prognosis One such potential new treatment strategy centers on Notch signaling [6,7]. This evolutionarily conserved pathway, which regulates a wide range of cellular processes, including cell proliferation, cell fate, and progenitor differentiation [8,9,10], plays an important role in melanoma. It does so by promoting tumor proliferation [11,12,13,14], invasion [11,13,15] and immunosuppression [6,14]. The reciprocal interactions between Notch signaling and melanocyte lineage-specific pathways have been understudied, information necessary for realizing the Notch pathway’s therapeutic potential
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