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Nuclear Localization of Yes-Associated Protein Is Associated With Tumor Progression in Cutaneous Melanoma

 Hyang Joo Ryu  ;  Chayeon Kim  ;  Hyenguk Jang  ;  Sun Il Kim  ;  Sang Joon Shin  ;  Kee Yang Chung  ;  Carlos Torres-Cabala  ;  Sang Kyum Kim 
 LABORATORY INVESTIGATION, Vol.104(5) : 102048, 2024-05 
Journal Title
Issue Date
Adaptor Proteins, Signal Transducing* / genetics ; Adaptor Proteins, Signal Transducing* / metabolism ; Adult ; Aged ; Animals ; Cell Line, Tumor ; Cell Nucleus* / metabolism ; Cell Proliferation ; Disease Progression ; Female ; Humans ; Male ; Melanoma* / metabolism ; Melanoma* / pathology ; Melanoma, Cutaneous Malignant ; Mice ; Mice, Nude ; Middle Aged ; Phosphoproteins / metabolism ; Skin Neoplasms* / metabolism ; Skin Neoplasms* / pathology ; Transcription Factors* / metabolism ; YAP-Signaling Proteins* / metabolism
invasion ; melanoma ; nuclear expression ; proliferation ; verteporfin ; yes-associated protein
Yes-associated protein (YAP), an effector molecule of the Hippo signaling pathway, is expressed at high levels in cutaneous melanoma. However, the role of YAP in melanoma progression according to cellular localization is poorly understood. Tissues from 140 patients with invasive melanoma were evaluated by immunohistochemistry. Flow cytometry, western blotting, viability assays, wound healing assays, verteporfin treatment, and xenograft assays were conducted using melanoma cell lines B16F1 and B16F10 subjected to YapS127A transfection and siYap knockdown. Nuclear YAP localization was identified in 63 tumors (45.0%) and was more frequent than cytoplasmic YAP in acral lentiginous and nodular subtypes (P =.007). Compared with cytoplasmic YAP melanomas, melanomas with nuclear YAP had higher mitotic activity (P =.016), deeper invasion (P <.001), and more frequently metastasized to lymph nodes (P <.001) and distant organs (P <.001). Patients with nuclear YAP melanomas had poorer disease-free survival (P <.001) and overall survival (P <.001). Nuclear YAP was an independent risk factor for distant metastasis (hazard ratio: 3.206; 95% CI: 1.032-9.961; P =.044). Proliferative ability was decreased in siYapB16F1 (P <.001) and siYapB16F10 (P =.001) cells and increased in YapS127AB16F1 (P =.003) and YapS127AB16F10 (P =.002) cells. Cell cycle analysis demonstrated relative G1 retention in siYapB16F1 (P <.001) and siYapB16F10 (P <.001) cells and S retention in YapS127AB16F1 cells (P =.008). Wound healing assays showed that Yap knockdown inhibited cell invasion (siYapB16F1, P =.001; siYapB16F10, P <.001), whereas nuclear YAP promoted it (YapS127AB16F, P <.001; YapS127AB16F1, P =.017). Verteporfin, a direct YAP inhibitor, reduced cellular proliferation in B16F1 (P =.003) and B16F10 (P <.001) cells. Proliferative effects of nuclear YAP were confirmed in xenograft mice (P <.001). In conclusion, nuclear YAP in human melanomas showed subtype specificity and correlated with proliferative activity and proinvasiveness. It is expected that YAP becomes a useful prognostic marker, and its inhibition may be a potential therapy for melanoma patients. © 2024 The Authors
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1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Sang Kyum(김상겸) ORCID logo https://orcid.org/0000-0003-0768-9923
Ryu, Hyang-Joo(류향주)
Shin, Sang Joon(신상준) ORCID logo https://orcid.org/0000-0001-5350-7241
Chung, Kee Yang(정기양) ORCID logo https://orcid.org/0000-0003-3257-0297
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