A Transcriptionally Inactive ATF2 Variant Drives Melanomagenesis

• Transcriptionally inactive ATF2 (Atf2Δ8,9) induces pigmentation
• Atf2Δ8,9 induces melanoma in BrafV600E mice
• Genes implicated in immune cell recruitment and metastasis are induced by Atf2Δ8,9
• Human ATF2 splice variant 5 phenocopies Atf2Δ8,9 and coincides with poor prognosis

SummaryMelanoma 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 (Atf2Δ8,9) promotes development of melanoma in mouse models. Atf2Δ8,9-driven tumors show enhanced pigmentation, immune infiltration, and metastatic propensity. Similar to mouse Atf2Δ8,9, we have identified a transcriptionally inactive human ATF2 splice variant 5 (ATF2SV5) that enhances the growth and migration capacity of cultured melanoma cells and immortalized melanocytes. ATF2SV5 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.

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