PURPL Represses Radiation-Induced Apoptosis to Promote Radioresistance in Cutaneous Melanoma by Direct Interfering With BID Cleavage

Abstract

The rise of radioresistance in treating cutaneous melanoma challenges the efficacy of radiotherapy. Transcriptomic sequencing highlights PURPL as one of the top upregulated long noncoding RNAs in response to ionizing radiation (IR) treatment in melanoma cells, suggesting its role in radioresistance. To explore such hypothesis, loss-of-function experiments were conducted to assess the impact of PURPL on melanoma cell viability, colony formation, and migration. Mechanistic studies using RNA pulldown identified BID as the interacting protein partner of PURPL. Further analysis explored the relationship among PURPL, BID, and Caspase-8 in the context of IR-induced DNA damage and apoptosis through loss-of- and gain-of-function experiments. The findings demonstrated that silencing PURPL significantly repressed melanoma cell viability, colony formation, migration, and invasiveness, indicating its potential role in promoting radioresistance. Moreover, PURPL was shown to repress IR-induced DNA damage and apoptosis, supporting its involvement in melanoma radioresistance. Mechanistically, PURPL inhibited the interaction between BID and Caspase-8, thereby modulating the mitochondrial apoptosis pathway and promoting radioresistance. In conclusion, this study provides evidence supporting the pro-radioresistance role of PURPL in melanoma. In vivo assays further corroborated the in vitro findings, highlighting the potential clinical relevance of targeting PURPL in radioresistant melanoma. By interfering with the association between BID and Caspase-8, PURPL may serve as a novel therapeutic target for clinical radiotherapy during the treatment of melanoma.