IL-1β expression driven by androgen receptor absence or inactivation promotes prostate cancer bone metastasis.

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.

Cancer research communications. 2022 Dec 02 [Epub]

Anthony DiNatale, Asurayya Worrede, Waleed Iqbal, Michael Marchioli, Allison Toth, Martin Sjöström, Xiaolin Zhu, Eva Corey, Felix Y Feng, Wanding Zhou, Alessandro Fatatis

Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA., Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Department of Radiation Oncology, UCSF, San Francisco, CA., Department of Urology, University of Washington, WA.