Meißgeier Tina, Kappelmann-Fenzl Melanie, Staebler Sebastian, Ahari Ata Jadid, Mertes Christian, Gagneur Julien, Linck-Paulus Lisa, Bosserhoff Anja Katrin
Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany.
Faculty of Computer Science, Deggendorf Institute of Technology, Deggendorf, Germany.
Cell Prolif. 2025 Feb;58(2):e13741. doi: 10.1111/cpr.13741. Epub 2024 Aug 30.
Abnormalities in alternative splicing are a hallmark of cancer formation. In this study, we investigated the role of the splicing factor PHD finger protein 5A (PHF5A) in melanoma. Malignant melanoma is the deadliest form of skin cancer, and patients with a high PHF5A expression show poor overall survival. Our data revealed that an siRNA-mediated downregulation of PHF5A in different melanoma cell lines leads to massive splicing defects of different tumour-relevant genes. The loss of PHF5A results in an increased rate of apoptosis by triggering Fas- and unfolded protein response (UPR)-mediated apoptosis pathways in melanoma cells. These findings are tumour-specific because we did not observe this regulation in fibroblasts. Our study identifies a crucial role of PHF5A as driver for melanoma malignancy and the described underlying splicing network provides an interesting basis for the development of new therapeutic targets for this aggressive form of skin cancer.
可变剪接异常是癌症形成的一个标志。在本研究中,我们调查了剪接因子PHD指蛋白5A(PHF5A)在黑色素瘤中的作用。恶性黑色素瘤是最致命的皮肤癌形式,PHF5A高表达的患者总体生存率较差。我们的数据显示,在不同的黑色素瘤细胞系中,siRNA介导的PHF5A下调会导致不同肿瘤相关基因出现大量剪接缺陷。PHF5A的缺失通过触发黑色素瘤细胞中Fas和未折叠蛋白反应(UPR)介导的凋亡途径,导致凋亡率增加。这些发现具有肿瘤特异性,因为我们在成纤维细胞中未观察到这种调控。我们的研究确定了PHF5A作为黑色素瘤恶性肿瘤驱动因子的关键作用,所描述的潜在剪接网络为开发针对这种侵袭性皮肤癌的新治疗靶点提供了有趣的基础。