Malignant melanoma is a fatal cancer with high metastatic characteristics. Approximately 80% of skin cancer deaths are caused by metastatic melanoma. It has been established that the metastatic ability of melanoma is regulated by an intricate gene interconnection network. Thus, the aim of this study was to identify and validate hub genes associated with metastatic melanoma and to further illustrate its potential mechanisms.

The method of weighted gene coexpression network analysis (WGCNA) was applied to explore potential regulatory targets and investigate the relationship between the key module and hub genes associated with the metastasis ability of melanoma.

In the turquoise module, 26 hub genes were initially selected, and 6 of them were identified as “real” hub genes with high connectivity in the protein-protein interaction network. In terms of validation, PKP1 had the highest correlation with metastasis among all the “real” hub genes. Data obtained from the GEPIA database and the Gene Expression Omnibus database showed a lower expression of PKP1 in melanoma tissues compared to normal skin tissues. The results also showed that PKP1 was downregulated in metastatic melanomas (n = 367) compared with primary melanomas (n = 103) in The Cancer Genome Atlas (TCGA) database (n = 470). Furthermore, an ROC curve showed that PKP1 expression had good power in the diagnostics of both primary melanoma (p =  5.30e-06, AUC = 0.8) and metastatic melanoma (p =  1.13e-10, AUC = 0.925). We also found that PKP1 could distinguish low- and high-grade of metastatic melanomas and was associated with inflammatory melanoma. Moreover, in a tumor-bearing mouse model, melanoma tissues also showed lower mRNA expression of PKP1 than the adjacent normal skin. Finally, Gene Set Enrichment Analysis indicated that the calcium signaling was significantly enriched in metastatic melanoma with highly expressed PKP1.

PKP1 was identified as a new potential tumor suppressor in human melanoma, likely through regulating calcium signaling pathways.