Abstract
The ubiquitin-specific protease 7 (USP7), as a deubiquitinating enzyme, plays an important role in tumor progression by various mechanisms and serves as a potential therapeutic target. However, the functional role of USP7 in melanoma remains elusive. Here, we found that USP7 is overexpressed in human melanoma by tissue microarray. We performed TMT-based quantitative proteomic analysis to evaluate the A375 human melanoma cells treated with siRNA of USP7. Our data revealed specific proteins as well as multiple pathways and processes that are impacted by USP7. We found that the phosphatidylinositol-3-kinases/Akt (PI3K-Akt), forkhead box O (FOXO), and AMP-activated protein kinase (AMPK) signaling pathways may be closely related to USP7 expression in melanoma. Moreover, knockdown of USP7 in A375 cells, particularly USP7 knockout using CRISPR-Cas9, verified that USP7 regulates cell proliferation in vivo and in vitro. The results showed that inhibition of USP7 increases expression of the AMPK beta (PRKAB1), caspase 7(CASP7), and protein phosphatase 2 subunit B R3 isoform (PPP2R3A), while attenuating expression of C subunit of vacuolar ATPase (ATP6V0C), and peroxisomal biogenesis factor 11 beta (PEX11B). In summary, these findings reveal an important role of USP7 in regulating melanoma progression via PI3K/Akt/FOXO and AMPK signaling pathways and implicate USP7 as an attractive anticancer target for melanoma.
Highlights
Malignant melanomas are an extremely aggressive skin cancer induced by ultraviolet (UV) radiation that arises from melanocytes [1]
We found that the expression of the ubiquitin-specific protease 7 (USP7) protein was increased in melanoma tissues compared with normal tissue by immunohistochemistry (Figures 1A, B)
The results showed that USP7 expression was negatively correlated with overall survival of melanoma patients in the The Cancer Genome Atlas (TCGA) dataset (P < 0.05, Figure 1C)
Summary
Malignant melanomas are an extremely aggressive skin cancer induced by ultraviolet (UV) radiation that arises from melanocytes [1]. In the past decades, researchers have explored its effects on tissues including the bladder [15], prostate [12], colon [16], lung [17], liver [18], ovary [19], brain [14], breast [20], and glioma [21]. All these studies demonstrated that the role of USP7 is tumor suppressive or oncogenic, depending on the context of the cancers and its substrates. The expression and role of USP7 in melanoma remains to be elucidated
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