Melanoma prognoses dramatically worsen following metastasis. Determining metastatic drivers supports using novel drugs targeting this grim progression. We uncovered a regulatory network where transcription factor AP-2alpha supports melanoma metastasis by activating interrelated pro-survival genes. This culminates in AP-2alpha-mediated upregulation of EZH2, a pro-metastatic histone methyltransferase. A highly specific EZH2 inhibitor halts metastatic behaviors of melanoma cells and elicits a heritable abolishment of metastasis in vivo, supporting its efficacy as an anti-metastatic therapy for advanced melanoma.