PGC1 alpha coactivates ERG fusion to drive antioxidant target genes under metabolic stress

Abstract

The presence of ERG gene fusion; from developing prostatic intraepithelial neoplasia (PIN) lesions to hormone resistant high grade prostate cancer (PCa) dictates disease progression, altered androgen metabolism, proliferation and metastasis1–3. ERG driven transcriptional landscape may provide pro-tumorigenic cues in overcoming various strains like hypoxia, nutrient deprivation, inflammation and oxidative stress. However, insights on the androgen independent regulation and function of ERG during stress are limited. Here, we identify PGC1α as a coactivator of ERG fusion under various metabolic stress. Deacetylase SIRT1 is necessary for PGC1α-ERG interaction and function. We reveal that ERG drives the expression of antioxidant genes; SOD1 and TXN, benefitting PCa growth. We observe increased expression of these antioxidant genes in patients with high ERG expression correlates with poor survival. Inhibition of PGC1α-ERG axis driven transcriptional program results in apoptosis and reduction in PCa xenografts. Here we report a function of ERG under metabolic stress which warrants further studies as a therapeutic target for ERG fusion positive PCa.