NUMB as a Therapeutic Target for Melanoma

Hristova, Denitsa M.; Fukumoto, Takeshi; Takemori, Chihiro; Gao, Le; Xia, Hua; Wang, Joshua X.; Li, Ling; Beqiri, Marilda; Watters, Andrea; Vultur, Adina; Gimie, Yusra; Rebecca, Vito W.; Samarkina, Anastasia; Jimbo, Haruki; Nishigori, Chikako; Zhang, Jie; Cheng, Chaoran; Wei, Zhi; Somasundaram, Rajasekharan; Fukunaga-Kalabis, Mizuho; Herlyn, Meenhard

doi:10.1016/j.jid.2021.11.027

Cited by 7 publications

(6 citation statements)

References 51 publications

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“…Additionally, these results might be influenced by MITF (Microphthalmia-associated transcription factor) signaling, an important factor in melanoma EMT as A375 and SK-MEL-2 cells are MITF low and WM115 cells has MITF high phenotype 32 , 33 . Additionally, these results are in line with other published studies in which NUMB modulation did not affect the proliferation of melanoma cells 7 , and NUMB isoform 1 inhibited migration and invasion by preventing EMT in esophageal cancer 34 . However, these changes appear to be independent of NOTCH activation as we did not observe a significant change in NICD expression upon NUMB modulation in melanoma cells.…”

Section: Discussionsupporting

confidence: 92%

“…On the molecular level, EMT can be recognized by the reduced expression of epithelial markers such as E-cadherin and some cytokeratin isoforms, and the elevated expression of mesenchymal markers such as N-cadherin, and Vimentin 12 . Importantly, the loss of cell–cell contacts and the reorganization of the intracellular cytoskeleton during EMT result in increased cell migration and invasion 7 , which allows cells to invade the surrounding stroma and vasculature, thereby leading to tumor dissemination and metastases. Despite the non-epithelial nature of melanoma cells, similar EMT characteristics, including an E-cadherin/N-cadherin switch, have been shown to promote melanoma invasion and metastasis 22 – 24 .…”

Section: Discussionmentioning

confidence: 99%

“…In a very recent study, NUMB expression was shown to be downregulated in metastatic melanoma cells. Further, the knockdown of NUMB significantly increased the invasion potential of melanoma cells in vitro and in the lungs of a mouse model in vivo by modulating the NOTCH target gene CCNE 7 . Interestingly, the NUMB gene is alternatively spliced to generate six functionally distinct transcript variants (isoforms), out of which four transcript variants NUMB1-651 aa; NUMB2-603 aa; NUMB3-640 aa; NUMB4-592 aa, are the most prevalent 8 .…”

Section: Introductionmentioning

confidence: 95%

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Role of PLK1/NUMB/NOTCH in epithelial-mesenchymal transition in human melanoma

Chhabra,

Singh,

Ndiaye

et al. 2024

npj Precis. Onc.

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Polo-like kinase 1 (PLK1), a serine/threonine kinase, is overexpressed in melanoma and its expression has been associated with poor disease prognosis. PLK1 has been shown to interact with NUMB, a NOTCH antagonist. However, the exact role of PLK1, NUMB, and NOTCH signaling in epithelial-mesenchymal transition (EMT) in melanoma progression is unclear. In this study, Affymetrix microarray analysis was performed to determine differentially expressed genes following shRNA-mediated knockdown of PLK1 in human melanoma cells that showed significant modulations in EMT and metastasis-related genes. Using multiple PLK1-modulated melanoma cell lines, we found that PLK1 is involved in the regulation of cell migration, invasion, and EMT via its kinase activity and NOTCH activation. In vitro kinase assay and mass spectrometry analysis demonstrated a previously unknown PLK1 phosphorylation site (Ser413) on NUMB. Overexpression of non-phosphorylatable (S413A) and phosphomimetic (S413D) mutants of NUMB in melanoma cells implicated the involvement of NUMB-S413 phosphorylation in cell migration and invasion, which was independent of NOTCH activation. To determine the clinical relevance of these findings, immunohistochemistry was performed using melanoma tissue microarray, which indicated a strong positive correlation between PLK1 and N-cadherin, a protein required for successful EMT. These findings were supported by TCGA analysis, where expression of high PLK1 with low NUMB or high NOTCH or N-cadherin showed a significant decrease in survival of melanoma patients. Overall, these results suggest a potential role of PLK1 in EMT, migration, and invasion of melanoma cells. Our findings support the therapeutic targeting of PLK1, NUMB, and NOTCH for melanoma management.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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Role of PLK1/NUMB/NOTCH in epithelial-mesenchymal transition in human melanoma

Chhabra,

Singh,

Ndiaye

et al. 2024

npj Precis. Onc.

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“…It has previously been shown that miR‐146a‐5p down‐regulates NUMB leading to melanoma initiation and progression by activating the Notch signalling pathway (Forloni et al., 2014 ). Furthermore, data from The Cancer Genome Atlas (TCGA) also show a correlation between poor survival in melanoma patients and low NUMB expression levels (Hristova et al., 2021 ).…”

Section: Resultsmentioning

confidence: 99%

“…We identified the mRNA NUMB as a direct binding partner of miR‐146a‐5p. This is important since Numb is an inhibitor protein in the Notch signalling pathway, known to be implicated in melanoma pathogenesis (Hristova et al., 2021 ). Therefore, our findings strongly suggest that miR‐146a‐5p is important in MBM development and thus represents a therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of extracellular vesicle‐derived miR‐146a‐5p decreases progression of melanoma brain metastasis via Notch pathway dysregulation in astrocytes

Rigg,

Wang,

Xue

et al. 2023

J of Extracellular Vesicle

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Melanoma has the highest propensity of all cancers to metastasize to the brain with a large percentage of late‐stage patients developing metastases in the central nervous system (CNS). It is well known that metastasis establishment, cell survival, and progression are affected by tumour‐host cell interactions where changes in the host cellular compartments likely play an important role. In this context, miRNAs transferred by tumour derived extracellular vesicles (EVs) have previously been shown to create a favourable tumour microenvironment. Here, we show that miR‐146a‐5p is highly expressed in human melanoma brain metastasis (MBM) EVs, both in MBM cell lines as well as in biopsies, thereby modulating the brain metastatic niche. Mechanistically, miR‐146a‐5p was transferred to astrocytes via EV delivery and inhibited NUMB in the Notch signalling pathway. This resulted in activation of tumour‐promoting cytokines (IL‐6, IL‐8, MCP‐1 and CXCL1). Brain metastases were significantly reduced following miR‐146a‐5p knockdown. Corroborating these findings, miR‐146a‐5p inhibition led to a reduction of IL‐6, IL‐8, MCP‐1 and CXCL1 in astrocytes. Following molecular docking analysis, deserpidine was identified as a functional miR‐146a‐5p inhibitor, both in vitro and in vivo. Our results highlight the pro‐metastatic function of miR‐146a‐5p in EVs and identifies deserpidine for targeted adjuvant treatment.

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