We report the inverse association between the expression of androgen receptor (AR) and interleukin-1beta (IL-1β) in a cohort of patients with metastatic castration resistant prostate cancer (mCRPC). We also discovered that AR represses the IL-1β gene by binding an androgen response element (ARE) half-site located within the promoter, which explains the IL-1β expression in AR-negative (ARNEG) cancer cells. Consistently, androgen-depletion or AR-pathway inhibitors (ARIs) de-repressed IL-1β in ARPOS cancer cells, both in vitro and in vivo. The AR transcriptional repression is sustained by histone de-acetylation at the H3K27 mark in the IL-1β promoter. Notably, patients' data suggest that DNA methylation prevents IL-1β expression, even if the AR-signaling axis is inactive. Our previous studies show that secreted IL-1β supports metastatic progression in mice by altering the transcriptome of tumor-associated bone stroma. Thus, in prostate cancer patients harboring ARNEG tumor cells or treated with ADT/ARIs, and with the IL-1β gene unmethylated, IL-1β could condition the metastatic microenvironment to sustain disease progression.
Keywords: Androgen Receptor; IL-1β; Metastasis; Methylation; Prostate Cancer.