Hypoxia-induced S-phase kinase-interacting protein 2 knockdown repressed the progression of melanoma through extracellular signal-regulated kinase 1/2 pathway

Objective: Hypoxia intensely drives the development of malignant tumors, including skin cutaneous melanoma (SKCM). S-phase kinase-interacting protein 2 (SKP2) is known to participate in the progression of human tumors. The purpose of this study is to explore whether SKP2 acts as a hypoxic response gene during SKCM progression. Material and Methods: SKP2 expression in SKCM tissues was analyzed using The Cancer Genome Atlas database. Anoxic experiments were conducted to simulate an anoxic environment. 5-Ethynyl-2'-deoxyuridine and colony formation assays were used to evaluate SKCM cell growth. Scratch healing and Transwell assays were applied to measure the migration and invasion abilities of SKCM cells. An immunoblotting assay was used to detect the levels of extracellular signal-regulated kinase (ERK)1/2 pathway proteins. In addition, the ERK-specific agonist LM22B-10 was added to confirm whether the ERK1/2 signaling pathway is required for SKP2-mediated SKCM progression under hypoxic conditions. Results: SKP2 was significantly upregulated in SKCM tissues and closely related to adverse outcomes in patients. Moreover, SKP2 levels increased in SKCM cells under normoxic conditions and further elevated under hypoxic conditions. SKP2 deficiency led to the reduced proliferation, migration, and invasion potential of cells under hypoxic conditions. Mechanically, SKP2 silencing blocked the ERK1/2 pathway in hypoxic cells, and the activation of the ERK1/2 pathway rescued the suppression effect of SKP2 on the hypoxia-induced progression of SKCM. Conclusion: SKP2 deficiency repressed the hypoxic-induced progression of SKCM through the ERK1/2 pathway. This novel discovery regarding the SKP2/ERK1/2 axis might provide new insights into the pathogenesis of SKCM.