CirROR1 upregulates CCNE1 expression to promote melanoma invasion and metastasis by recruiting KAT2A

Abstract Circular RNAs (circRNAs) play important roles in cancer occurrence and progression. However, the clinical significance of specific circRNAs in melanoma and the underlying molecular mechanisms remain unclear. In this study, we found that CircROR1 was upregulated in metastatic melanoma cells and tissues, and gain-or loss-of-function assays showed that CircROR1 promoted melanoma cell proliferation, invasion, metastasis in vitro and in vivo. The intersection of mRNA microarray data and GEO datasets, as well as subsequent qRT‒PCR and Western blotting validation, confirmed that CCNE1 was a potential downstream target gene of CircROR1. Moreover, we demonstrated that CCNE1 was highly expressed in metastatic melanoma tissues, and high CCNE1 expression was associated with poor survival. CCNE1 knockdown partially attenuated the CircROR1 overexpression-induced increases in cell proliferation, invasion and metastasis, simultaneously decreasing the high expression of MMP9 and increasing the low expression of TIMP2. Thus, CircROR1 plays a role in promoting malignant progression through CCNE1. Mechanistically, RNA pull-down and RIP assays indicated that CircROR1 bound to the KAT2A protein in the nucleus. ChIP assays showed that CircROR1 increased the enrichment of H3K9ac acetylation in the CCNE1 promoter, thereby upregulating CCNE1 expression. In conclusion, CircROR1 upregulates CCNE1 expression through KAT2A-mediated histone acetylation. Our research confirms the critical role of CircROR1 in melanoma invasion and metastasis, and CircROR1 could serve as a potential therapeutic target for melanoma treatment.