Epigenetic silencing of CDR1as drives IGF2BP3-mediated melanoma invasion and metastasis [RNA-Seq]

Metastasis is the primary cause of death of cancer patients. Dissecting mechanisms governing metastatic spread may uncover important tumor biology and/or yield promising therapeutic insights. Here we investigated the role of circular RNAs (circRNA) in metastasis, using melanoma as a model aggressive tumor. We identified silencing of Cerebellar Degeneration Related 1 (CDR1as), a regulator of the microRNA miR-7, as a hallmark of melanoma progression. We find that CDR1as depletion results from epigenetic silencing of its originating lincRNA, and promotes invasion in vitro and metastasis in vivo, through a miR-7-independent, IGF2BP3-mediated mechanism. Moreover, CDR1as levels identify cellular states associated with distinct therapeutic responses. Our study reveals functional, prognostic and predictive roles for CDR1as and expose circRNAs as key players in metastasis. circRNA profiling analyses were performed on rRNA-depleted RNA-seq of 10 melanoma STCs (single replicates) and 4 cultured melanocytes (single replicates, from ENCODE). rRNA-depleted RNA-seq of additional cultured melanocytes (single replicates of 5 melanocyte cultures from independent donors), melanoma STCs (single replicates of 3 primary-derived STCs), and established melanoma cell lines (2-5 replicates of 7 cell lines) were analyzed for expression of CDR1as and LINC00632. RNA-seq was performed on control and CDR1as-depleted WM278 melanoma cells.