<scp>ZNF224</scp> enhances the oncogenic function of p21 via p53 and <scp>AKT</scp> pathways in melanoma

Expression of zinc finger protein 224 (ZNF224) is deregulated in various hematological and solid cancers, where its high protein levels correlate well with faster progression and worse prognosis due to activation of oncogenic pathways involved in promoting cell growth and survival, inhibiting apoptosis, and sustaining invasion and metastasis. In previous works, we identified ZNF224 as one of the mediators of the transforming growth factor beta (TGF-β)-induced pro-tumoral activities in melanoma. In the present study, we thoroughly investigated the molecular mechanisms underlying the oncogenic role of ZNF224 in this kind of cancer. We demonstrated that ZNF224 overexpression caused increased cell growth and reduced drug-mediated apoptosis by enhancing the dysregulated function of cyclin-dependent kinase inhibitor 1 [p21(CIP1/WAF1), also known as CDKN1A]. We provide strong evidence that ZNF224 overexpression in melanoma cell lines positively modulated p21(CIP1/WAF1) gene transcription in a p53-dependent manner and enhanced AKT-triggered p21(CIP1/WAF1) oncogenic effects through its protein cytosolic retention, inhibiting apoptosis and favoring cell proliferation. Analysis of transcriptomic data from human melanoma tissue samples confirmed a close relationship between p21(CIP1/WAF1) and ZNF224 in cells, at least as long as p53 functionality is maintained. The tumorigenic molecular mechanism involving ZNF224, identified in this study, provides new insights into understanding melanoma development and progression, breaking ground in the research for new therapeutic tools.