The Breast Cancer Oncogene EMSY Represses Transcription of Antimetastatic microRNA miR-31

Amplification of the EMSY gene in sporadic breast and ovarian cancers is a poor prognostic indicator. Although EMSY has been linked to transcriptional silencing, its mechanism of action is unknown. Here, we report that EMSY acts as an oncogene, causing the transformation of cells in vitro and potentiating tumor formation and metastatic features in vivo. We identify an inverse correlation between EMSY amplification and miR-31 expression, an antimetastatic microRNA, in the METABRIC cohort of human breast samples. Re-expression of miR-31 profoundly reduced cell migration, invasion, and colony-formation abilities of cells overexpressing EMSY or haboring EMSY amplification. We show that EMSY is recruited to the miR-31 promoter by the DNA binding factor ETS-1, and it represses miR-31 transcription by delivering the H3K4me3 demethylase JARID1b/PLU-1/KDM5B. Altogether, these results suggest a pathway underlying the role of EMSY in breast cancer and uncover potential diagnostic and therapeutic targets in sporadic breast cancer. [Display omitted] •EMSY is an oncogene that represses miR-31 transcription in a BRCA2-independent manner•Re-expression of miR-31 abrogates EMSY-mediated effects on cell migration in vitro•EMSY and miR-31 levels anticorrelate in human breast samples from the METABRIC cohort•EMSY, ETS-1, and KDM5B co-occupy miR-31 promoter and repress its transcription EMSY gene amplification is an indicator of breast and ovarian cancers. Viré et al. report that EMSY is an oncogene that functions by repressing the transcription of antimetastatic miR-31. Repression involves the transcription factor ETS-1 and the histone demethylase KDM5B. miR-31 is a key player in cancer-related EMSY function because miR-31 expression reduces EMSY-mediated oncogenicity.