PAF15 drives melanoma progression by promoting proliferation concomitant with suppression of DNA damage and apoptosis: a novel therapeutic vulnerability.

Abstract

PAF15 is an oncogene and is overexpressed across multiple malignancies. However, its biological role in melanoma remains largely unclear. In this research, bioinformatics analysis (GEPIA2, TCGA, CancerSEA) confirmed transcriptional PAF15 overexpression in melanoma, correlating with a poor prognosis and implicating pathways involved in cell cycle, proliferation, DNA damage, and repair. Immunohistochemical analysis further confirmed high expression of PAF15 protein in clinical melanoma tissues. Subsequently, the impact of PAF15 on melanoma cell proliferation and cell cycle progression was quantified through MTT assay and propidium iodide staining. Annexin V staining and immunofluorescence were used to assess apoptosis and DNA damage. Markers associated with these biological pathways were evaluated by western blot. Evaluation of PAF15-mediated tumorigenic effects was performed using a subcutaneous xenograft model. The results revealed that PAF15 knockdown markedly suppressed melanoma cell proliferation through the induction of G0/G1 phase cell cycle arrest. Additionally, PAF15 knockdown triggered genomic instability, as evidenced by increased DNA damage markers, and promoted caspase-dependent apoptosis. Furthermore, PAF15 knockdown suppressed the growth of xenograft tumors in vivo. Notably, these tumor-inhibiting effects of PAF15 knockdown were effectively rescued upon PAF15 reconstitution. Summed up, these findings establish PAF15 as both a prognostic indicator for unfavorable clinical outcomes and a promising therapeutic vulnerability in melanoma.