The AKT-p21 phosphorylation signaling axis confers poor prognosis and dacarbazine resistance in melanoma.

Understanding the molecular mechanisms underlying melanoma metastasis and chemoresistance is crucial for predicting patients’ prognoses and developing more effective therapies. In this study, we investigated the role of p21 in melanoma progression and treatment resistance. Our findings reveal that increased gene and protein expression of p21 is a strong predictor of poor prognosis in human melanoma, while reducing p21 makes these cells more responsive to chemotherapy. Immunohistochemistry experiments showed higher levels of total and cytoplasmic p21 in metastatic melanoma compared to primary melanomas and other melanocytic lesions. In silico analysis highlighted the interaction of p21 with proteins based on their cellular localization, identifying AKT1 as a potential regulator of p21. This finding corresponds with the observed positive relationship between p21 and AKT1 levels in both melanoma cell lines and patient samples. Significantly, we observed that increased p21 expression, phosphorylation, and translocation to the cytoplasm are associated with resistance to the chemotherapy drug dacarbazine. Accordingly, the overexpression of p21 in a metastatic melanoma cell line led to a further increase in dacarbazine resistance, whereas downregulation of p21 sensitizes these cells to chemotherapy. In addition, both AKT downregulation and the pharmacological inhibition of PI3K diminished p21 phosphorylation, with the former intervention also sensitizing metastasis-prone cells to chemotherapy. Collectively, these findings highlight the critical role of the PI3K/AKT-p21 signaling in the regulation and subcellular localization of p21 in the context of chemotherapy resistance and melanoma prognosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-025-28984-6.