Epigenetic silencing of CDR1as drives IGF2BP3-mediated melanoma invasion and metastasis [RIP-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. Three biological replicates of IGF2BP3 RIP-sequencing was performed for WM278 control (shNTC) or CDR1as-depleted (shCDR1as) cells. Input and IGF2BP3 RIP samples were sequenced.