MicroRNAs and RNA-binding proteins (RBPs) primarily target the 3' UTR of mRNAs to control their translation and stability. However, their co-regulatory effects on specific mRNAs in physiology and disease are yet to be fully explored. CSDE1 is an RBP that promotes metastasis in melanoma and mechanisms underlying its oncogenic activities need to be completely defined. Here we report that CSDE1 interacts with specific miRNA-induced silencing complexes (miRISC) in melanoma. We find an association of CSDE1 with AGO2, the essential component of miRISC, which is facilitated by target mRNAs and depends on the first cold shock domain of CSDE1. Both CSDE1 and AGO2 bind to 3' UTR of PMEPA1. CSDE1 counters AGO2 binding, leading to an increase of PMEPA1 expression. We also identify a miRNA, miR-129-5p, that represses PMEPA1 expression in melanoma. Collectively, our results show that PMEPA1 promotes tumorigenic traits and that CSDE1 along with miR-129-5p/AGO2 miRISC act antagonistically to fine-tune PMEPA1 expression toward the progression of melanoma.