A Transcriptionally Inactive ATF2 Variant Drives Melanomagenesis

Summary Melanoma is one of the most lethal cutaneous malignancies, characterized by chemoresistance and a striking propensity to metastasize. The transcription factor ATF2 elicits oncogenic activities in melanoma, and its inhibition attenuates melanoma development. Here, we show that expression of a transcriptionally inactive form of Atf2 ( Atf2 Δ8,9 ) promotes development of melanoma in mouse models. Atf2 Δ8,9 -driven tumors show enhanced pigmentation, immune infiltration, and metastatic propensity. Similar to mouse Atf2 Δ8,9 , we have identified a transcriptionally inactive human ATF2 splice variant 5 ( ATF2 SV5 ) that enhances the growth and migration capacity of cultured melanoma cells and immortalized melanocytes. ATF2 SV5 expression is elevated in human melanoma specimens and is associated with poor prognosis. These findings point to an oncogenic function for ATF2 in melanoma development that appears to be independent of its transcriptional activity.