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Cancer Res Commun ; 2(12): 1545-1557, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36561929

RESUMO

We report the inverse association between the expression of androgen receptor (AR) and interleukin-1beta (IL-1ß) in a cohort of patients with metastatic castration resistant prostate cancer (mCRPC). We also discovered that AR represses the IL-1ß gene by binding an androgen response element (ARE) half-site located within the promoter, which explains the IL-1ß expression in AR-negative (ARNEG) cancer cells. Consistently, androgen-depletion or AR-pathway inhibitors (ARIs) de-repressed IL-1ß 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-1ß promoter. Notably, patients' data suggest that DNA methylation prevents IL-1ß expression, even if the AR-signaling axis is inactive. Our previous studies show that secreted IL-1ß 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-1ß gene unmethylated, IL-1ß could condition the metastatic microenvironment to sustain disease progression.


Assuntos
Neoplasias Ósseas , Neoplasias da Próstata , Humanos , Masculino , Animais , Camundongos , Receptores Androgênicos/genética , Interleucina-1beta/genética , Androgênios , Neoplasias da Próstata/genética , Transdução de Sinais/genética , Neoplasias Ósseas/genética , Microambiente Tumoral
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