Background: S‐phase kinase associated protein‐2 (Skp2) ubiquitin ligase p45^SKP2 is important in the degradation of p27^kip1 (a cyclin dependent kinase inhibitor) and progression through the G1‐S cell‐cycle checkpoint. Low levels of p27 and high levels of Skp2 are related to poor prognosis in some cancers.Methods: Clinicopathologic features and immunohistochemical expression of Skp2 and p27^kip1 were investigated in 198 melanocytic proliferations: 21 melanocytic nevi, 23 melanoma in situ, 119 primary melanoma, and 35 metastatic melanoma samples. Comparative and survival analyses were performed.Results: Progressive and significant increases and decreases in the nuclear expression of Skp2 and p27^kip1, respectively, was identified moving from melanocytic nevi (0.05 ± 0.2/85 ± 15) to melanoma in situ (3 ± 2/45 ± 20) to primary cutaneous melanoma (12 ± 9/30 ± 25) to metastatic melanoma (25 ± 15/15 ± 20) (p ≤ 0.006). Expression of these proteins also significantly correlated with increasing American Joint Committee on Cancer (AJCC) T (tumor) classification and AJCC stage (p ≤ 0.01). Moreover, the level of these two proteins exhibited a significant inverse relationship (r = −0.4, p = 0.0001). Skp2 cytoplasmic labeling index of >20% predicted worse 10‐year overall survival (38% vs. 86%, p = 0.04) in primary melanoma. Neither p27 nor Skp2 nuclear expression impacted significantly on prognosis.Conclusions: Gain of Skp2 and loss of p27^kip1 protein expression are implicated in melanoma progression where the level of p27^kip1 may be regulated by targeted proteolysis via Skp2. Cytoplasmic expression of Skp2 defines a subset of aggressive melanomas and could represent another pathway of deregulation of the cell cycle.

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