TY - JOUR
T1 - NUMB as a Therapeutic Target for Melanoma
AU - Hristova, Denitsa M.
AU - Fukumoto, Takeshi
AU - Takemori, Chihiro
AU - Gao, Le
AU - Hua, Xia
AU - Wang, Joshua X.
AU - Li, Ling
AU - Beqiri, Marilda
AU - Watters, Andrea
AU - Vultur, Adina
AU - Gimie, Yusra
AU - Rebecca, Vito
AU - Samarkina, Anastasia
AU - Jimbo, Haruki
AU - Nishigori, Chikako
AU - Zhang, Jie
AU - Cheng, Chaoran
AU - Wei, Zhi
AU - Somasundaram, Rajasekharan
AU - Fukunaga-Kalabis, Mizuho
AU - Herlyn, Meenhard
N1 - Funding Information:
The authors thank J. Hayden and F. Keeney (Wistar Imaging Facility) and D. Gourevitch (Wistar Histology Facility) and K. Tagawa (Kobe University, Kobe, Japan) for providing technical support. The research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers R21 CA191742 (MFK), RO1 CA238237 and CA259295 (MH), U54 CA224070 (MH), and PO1 CA114046 (MH); Dr Miriam and Sheldon G Adelson Medical Research Foundation; Japan Society for the Promotion of Science KAKENHI (grant number JP20309138, TF); the Okinaka Memorial Institute for Medical Research (TF); a research grant of the Japanese Association of Geriatric Dermatology (TF); The Nakatomi Foundation (TF); and Hoansha Foundation (TF). The support for Shared Resources utilized in this study was provided by the Cancer Center Support Grant CA010815 to The Wistar Institute (Philadelphia, PA). Support for core facilities utilized in this study was provided by the Cancer Center Support Grant CA010815 to the Wistar Institute.
Funding Information:
The authors thank J. Hayden and F. Keeney (Wistar Imaging Facility) and D. Gourevitch (Wistar Histology Facility) and K. Tagawa (Kobe University, Kobe, Japan) for providing technical support. The research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers R21 CA191742 (MFK), RO1 CA238237 and CA259295 (MH), U54 CA224070 (MH), and PO1 CA114046 (MH); Dr Miriam and Sheldon G Adelson Medical Research Foundation; Japan Society for the Promotion of Science KAKENHI (grant number JP20309138, TF); the Okinaka Memorial Institute for Medical Research (TF); a research grant of the Japanese Association of Geriatric Dermatology (TF); The Nakatomi Foundation (TF); and Hoansha Foundation (TF). The support for Shared Resources utilized in this study was provided by the Cancer Center Support Grant CA010815 to The Wistar Institute (Philadelphia, PA). Support for core facilities utilized in this study was provided by the Cancer Center Support Grant CA010815 to the Wistar Institute. Conceptualization: TF, MFK, MH; Formal Analysis: DMH, TF, CT, LG, XH, JXW, LL, MB, AW, AV, YG, VR, AS, HJ, CN, JZ, CC, ZW, RS, MFK, MH; Funding Acquisition: TF, MFK, MH; Investigation: DMH, TF, CT, LG, XH, JXW, LL, MB, AW, AV, YG, VR, AS, HJ, CN, JZ, CC, ZW, RS, MFK, MH; Methodology: DMH, TF, CT, LG, XH, JXW, LL, MB, AW, AV, YG, VR, AS, HJ, CN, JZ, CC, ZW, RS, MFK, MH; Resources: TF, MFK, MH; Supervision: TF, MFK, MH; Validation: DMH, TF, CT, LG, XH, JXW, LL, MB, AW, AV, YG, VR, AS, HJ, CN, JZ, CC, ZW, RS, MFK, MH; Visualization: DMH, TF, MFK, MH; Writing - Original Draft Preparation: DMH, TF, MFK, MH, The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2021 The Authors
PY - 2022/7
Y1 - 2022/7
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jid.2021.11.027
DO - 10.1016/j.jid.2021.11.027
M3 - Article
C2 - 34883044
AN - SCOPUS:85123374251
SN - 0022-202X
VL - 142
SP - 1882-1892.e5
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 7
ER -