NUMB as a Therapeutic Target for Melanoma.

Abstract

The 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. In this study, 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 three-dimensional 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 CCNE. Previous studies suggested that Wnt signaling increases NUMB expression. By mimicking Wnt stimulation through glycogen synthase kinase-3 inhibition, we increased NUMB expression in melanoma cells. Furthermore, a glycogen synthase kinase-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 through its regulation of the NOTCH‒CCNE axis and that the inhibitors that upregulate NUMB can exert therapeutic effects in melanoma.

• Authors: Denitsa M Hristova, Takeshi Fukumoto, Chihiro Takemori, Le Gao, Xia Hua, Joshua X Wang, Ling Li, Marilda Beqiri, Andrea Watters, Adina Vultur, Yusra Gimie, Vito Rebecca, Anastasia Samarkina, Haruki Jimbo, Chikako Nishigori, Jie Zhang, Chaoran Cheng, Zhi Wei, Rajasekharan Somasundaram, Mizuho Fukunaga-Kalabis, Meenhard Herlyn
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 142 Issue 7 Pg. 1882-1892.e5 (07 2022) ISSN: 1523-1747 [Electronic] United States
• PMID: 34883044 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Membrane Proteins
• Nerve Tissue Proteins
• NUMB protein, human
• Numb protein, mouse
• Glycogen Synthase Kinases

Topics

• Animals
• Cell Line, Tumor
• Glycogen Synthase Kinases (metabolism)
• Humans
• Melanoma (drug therapy, genetics)
• Membrane Proteins (genetics, metabolism)
• Mice
• Nerve Tissue Proteins (genetics, metabolism)
• Wnt Signaling Pathway