Inhibition of AURKB, regulated by pseudogene MTND4P12 , confers synthetic lethality to PARP inhibition in skin cutaneous melanoma

摘要

Despite significant advances, skin cutaneous melanoma (SKCM) is a common life-threatening cancer worldwide. Recently, pseudogenes have been discovered to be functional in many physiological processes and the pathogenesis of various diseases, including cancer. However, their relevance to SKCM remains largely unknown. In this study, seven upregulated pseudogenes were identified based on TCGA data. Among them, MTND4P12 was negatively correlated with the overall survival of SKCM patients. After constructing a pseudogene-miRNA-mRNA regulatory network, MTND4P12 was found to regulate the expression of oncogene AURKB by serving as a ceRNA. Both genetic and chemical inhibition of AURKB reduced viability and induced apoptosis of melanoma cells. Interestingly, DNA repair pathway seems to be involved in the anti-tumor effect of AURKB inhibition. Indeed, a synergistic therapeutic effect of AURKB inhibition and PARP inhibitor was confirmed both in vitro and in vivo. In conclusion, AURKB plays an oncogenic role and is a novel therapeutic target in SKCM. The combination of AURKB inhibition and PARP inhibitor has a synergistic effect, representing a promising treatment for SKCM.