STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pigmentation pathway

Metastatic melanomais hallmarked by its ability to switch oncogenic MITF expression. Here we tested the impact of STAT3on melanomaonset and progression in association with MITF expression levels. We established a mouse melanomamodel for deleting Stat3specifically in melanocytes with specific expression of human hyperactive NRASQ61K in an Ink4a deficient background. Mice with tissue specific Stat3deletion showed an early onset of disease, but displayed significantly diminished lung metastases. Whole genome expression profiling also revealed a reduced invasion phenotype, which was functionally confirmed in 3D melanomamodel systems. Notably, loss or knockdown of STAT3in mouse or human cells resulted in up-regulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3induced CEBPa/b expression was sufficient to suppress MITF transcription. Epigenetic analysis by ATAC-seqconfirmed that STAT3enabled CEBPa/b binding to the MITF enhancer region thereby silencing it. We conclude that STAT3is a metastasis driver in melanomaable to antagonize the MITF oncogene via direct induction of CEBPfamily member transcription facilitating RAS-RAF-driven melanomametastasis.