IL1β Expression Driven by Androgen Receptor Absence or Inactivation Promotes Prostate Cancer Bone Metastasis

Abstract

We report the inverse association between the expression of androgen receptor (AR) and IL1β in a cohort of patients with metastatic castration-resistant prostate cancer. We also discovered that AR represses the IL1β gene by binding an androgen response element half-site located within the promoter, which explains the IL1β expression in AR-negative (ARNEG) cancer cells. Consistently, androgen depletion or AR-pathway inhibitors (ARI) derepressed IL1β in AR-positive cancer cells, both in vitro and in vivo. The AR transcriptional repression is sustained by histone deacetylation at the H3K27 mark in the IL1β promoter. Notably, patients’ data suggest that DNA methylation prevents IL1β expression, even if the AR-signaling axis is inactive. Our previous studies show that secreted IL1β supports metastatic progression in mice by altering the transcriptome of tumor-associated bone stroma. Thus, in patients with prostate cancer harboring ARNEG tumor cells or treated with androgen-deprivation therapy/ARIs, and with the IL1β gene unmethylated, IL1β could condition the metastatic microenvironment to sustain disease progression. Significance: IL1β plays a crucial role in promoting skeletal metastasis. The current standard of care for patients with prostate cancer inhibits the AR-signaling axis in tumor cells and will consequently unleash IL1β production. Thus, hormonal deprivation and AR inhibitors should be combined with targeting IL1β signaling, and screening for DNA methylation on the IL1β locus will identify patients that benefit the most from this approach.