Direct ERG-to-glucocorticoid receptor interactions enhance tumorigenicity and might explain the enigmatic responses of prostate cancers to corticosteroids (ChIP-Seq)

Patients with prostate cancer (PCa) frequently express fusions between an androgen-regulated gene and anETSfamily gene, especiallyERG. Our protein complementation assays revealed that the glucocorticoid receptor, GR, physically interacts with ERG. This alleviates allosteric autoinhibition, stabilizes ERG and protects it from chemotherapy-induced degradation. Promoter-reporter assays indicated that GR transactivates ERG’s target genes, includingMYC. In PCa models, antagonizing GR or lowering cortisol increased apoptosis and decreased tumorigenic growth of ERG-positive, not ERG-negative PCa cells. Likewise, ERG+patient-derivedxenografts displayedintensifiedsensitivity tothe combination of aGRantagonist and an inhibitor of the androgen receptor (AR). In summary, we uncovered an oncogenic partner of ERG, identified a potential molecular basis for the association of corticosteroid use with poor responses to AR signaling inhibitors, as well as offer new strategies to treat a sizable group of patients with PCa.