ZNF224 is a mediator of TGF-β pro-oncogenic function in melanoma

The zinc finger protein ZNF224 plays a dual role in cancer, operating as both tumour suppressor and oncogenic factor depending on cellular and molecular partners. In this research we investigated the role of ZNF224 in melanoma, a highly invasive and metastatic cancer, and provided evidence for the involvement of ZNF224 in the TGF-beta signalling as a mediator of the TGF-beta pro-oncogenic function. Our results showed that ZNF224, whose expression increased in melanoma cell lines after TGF-beta stimulation, potentiated the activation induced by TGF-beta on its target genes involved in epithelial-mesenchymal transition (EMT). Accordingly, overexpression of ZNF224 enhanced the tumourigenic properties of melanoma cells, promoting cell proliferation and invasiveness, whereas ZNF224 knockdown had the opposite effect. Moreover, ZNF224 positively modulates the expression of TGF-beta itself and its type 1 and 2 receptors (T beta R1 and T beta R2), thus highlighting a possible mechanism by which ZNF224 could enhance the endogenous TGF beta/Smad signalling. Our findings unveil a positive regulatory loop between TGF-beta and ZNF224 to promote EMT, consequently increasing the tumour metastatic potential.