Malignant melanoma (MM) is a highly aggressive subtype of skin cancer characterized by a poor prognosis, particularly in the advanced stages. Despite advancements in targeted therapy and immunotherapy, the survival rates for MM remain low, underscoring the need for new therapeutic targets. Pleckstrin homology domain‑containing family A member 4 (PLEKHA4), which has regulatory functions in pivotal cellular processes, has emerged as a potential target in melanoma. The present study aimed to investigate the role of PLEKHA4 in melanoma progression, focusing on its influence on the MAPK and Wnt/β‑catenin signaling pathways. Bioinformatics analysis revealed that PLEKHA4 was upregulated in melanoma tissues, whereas PLEKHA4 knockdown in melanoma cell lines (A375 and A2058) significantly inhibited cell proliferation and migration, enhanced apoptosis and inhibited tumor growth in vivo. Mechanistic studies demonstrated that PLEKHA4 may exert its effects by modulating the MAPK signaling pathway through interactions with key proteins, including ERK, JNK and MEK. Additionally, PLEKHA4 was shown to impact apoptosis by regulating caspase‑3, COX2 and p65. Additionally, β‑catenin nuclear translocation was affected via the Wnt pathway. Moreover, PLEKHA4 knockdown reduced cMyc ubiquitination, consequently promoting its degradation. The present findings suggested that PLEKHA4 could promote melanoma cell proliferation by regulating both the MAPK and Wnt/β‑catenin pathways, thereby proposing PLEKHA4 as a promising therapeutic target for MM. Further studies are warranted to elucidate the mechanisms underlying PLEKHA4‑mediated modulation of cMyc ubiquitination.

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