NUMB AS A NEW THERAPEUTIC TARGET FOR MELANOMA.

Upregulation of the adaptor protein NUMB triggers melanocytic differentiation from multipotent skin stem cells, which share many properties with aggressive melanoma cells. Although NUMB acts as a tumor suppressor in various human cancer types, little is known about its role in melanoma. Here, we investigated the role of NUMB in melanoma progression and its regulatory mechanism. Analysis of The Cancer Genome Atlas melanoma datasets revealed that high NUMB expression in melanoma tissues correlates with improved patient survival. Moreover, NUMB expression is downregulated in metastatic melanoma cells. NUMB knockdown significantly increased the invasion potential of melanoma cells in a 3D collagen matrix in vitro and in the lungs of a mouse model in vivo; it also significantly upregulated the expression of the NOTCH target gene Cyclin E (CCNE). Previous studies suggested that Wnt signaling increases NUMB expression. By mimicking Wnt stimulation via GSK-3 inhibition, we increased NUMB expression in melanoma cells. Furthermore, a GSK-3 inhibitor reduced the invasion of melanoma cells in a NUMB-dependent manner. Together, our results suggest that NUMB suppresses invasion and metastasis in melanoma, potentially via its regulation of the NOTCH-CCNE axis, and that inhibitors that upregulate NUMB can exert therapeutic effects in melanoma.