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IL-1β expression driven by androgen receptor absence or inactivation promotes prostate cancer bone metastasis
Ist Teil von
Cancer research communications, 2022-12, Vol.2 (12), p.1545-1557
Ort / Verlag
United States
Erscheinungsjahr
2022
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
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 (AR
) cancer cells. Consistently, androgen-depletion or AR-pathway inhibitors (ARIs) de-repressed IL-1β in AR
cancer cells, both
and
. 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 AR
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.