EPS-8 regulates human malignant melanoma development by activating the Hedgehog pathway via degradation of Ptch1

The epidermal growth factor receptor pathway substrate 8 (EPS-8) is a tumor-associated antigen that is frequently overexpressed in various types of human solid tumors and is associated with aggressiveness and poor prognosis. The role of EPS-8 in cutaneous malignant melanoma and its potential mechanism remains unknown.

EPS-8 expression, mutation immune infiltration, and the tumor microenvironment in melanoma were analyzed using various databases. Clinical samples were collected and melanoma cell viability, apoptosis and protein levels were detected using cell counting kit-8, colony formation, Hoechst 33258 staining, and Western blot. Meanwhile, xenograft tumor models in nude mice were produced to evaluate the effect of EPS-8 on malignant melanoma in vivo.

EPS-8 levels were highly expressed in melanoma and correlated with immune-infiltrating cells, immune-related scores, and immunotherapy. Additionally, in clinical malignant melanoma samples, the EPS-8 level was significantly higher in the malignant melanoma samples compared with adjacent normal tissue, and patients with a high expression of EPS-8 had significantly poor tumor differentiation and a high clinical stage. The overexpression of EPS-8 promoted the proliferation but inhibited the apoptosis of malignant melanoma cells. The knockdown of EPS-8 markedly inhibited the activation of the Hedgehog (Hh) pathway. Notably, the knockdown of Patched-1 (Ptch1) could attenuate the changes in proteins and mRNA level, cell proliferation, apoptosis, and tumor growth induced by the knockdown of EPS-8.

The overexpression of EPS-8 had impacts on the proliferation and apoptosis of cutaneous malignant melanoma cells. The degradation of Ptch1 contributed to the activation of the Hh pathway induced by EPS-8.