The Hippo pathway oncoprotein YAP promotes melanoma cell invasion and spontaneous metastasis.
Adaptor Proteins, Signal Transducing
/ genetics
Animals
Antibiotics, Antineoplastic
/ pharmacology
Cell Line, Tumor
Cell Movement
/ drug effects
Doxorubicin
/ pharmacology
Gene Expression Profiling
/ methods
Hippo Signaling Pathway
Humans
Lung Neoplasms
/ genetics
Melanoma
/ genetics
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Protein Serine-Threonine Kinases
/ genetics
RNA Interference
Signal Transduction
/ genetics
Skin Neoplasms
/ genetics
Transcription Factors
/ genetics
Xenograft Model Antitumor Assays
/ methods
YAP-Signaling Proteins
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
18
09
2019
accepted:
08
06
2020
revised:
31
05
2020
pubmed:
21
6
2020
medline:
1
12
2020
entrez:
21
6
2020
Statut:
ppublish
Résumé
Melanoma is a deadly form of skin cancer that accounts for a disproportionally large proportion of cancer-related deaths in younger people. Compared with most other skin cancers, a feature of melanoma is its high metastatic capacity, although the mechanisms that confer this are not well understood. The Hippo pathway is a key regulator of organ growth and cell fate that is deregulated in many cancers. To analyse the Hippo pathway in cutaneous melanoma, we generated a transcriptional signature of melanoma cells that overexpressed YAP, the key downstream Hippo pathway oncoprotein. YAP-mediated transcriptional activity varied in melanoma cell lines but did not cluster with known genetic drivers of melanomagenesis such as BRAF and NRAS mutations. Instead, it correlated strongly with published gene expression profiles linked to melanoma cell invasiveness and varied throughout the metastatic cascade in melanoma patient tumours. Consistent with this, YAP was both necessary and sufficient for melanoma cell invasion in vitro. In vivo, YAP promoted spontaneous melanoma metastasis, whilst the growth of YAP-expressing primary tumours was impeded. Finally, we identified the YAP target genes AXL, THBS1 and CYR61 as key mediators of YAP-induced melanoma cell invasion. These data suggest that YAP is a critical regulator of melanoma metastasis.
Identifiants
pubmed: 32561850
doi: 10.1038/s41388-020-1362-9
pii: 10.1038/s41388-020-1362-9
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Antibiotics, Antineoplastic
0
Transcription Factors
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
Doxorubicin
80168379AG
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5267-5281Références
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