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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
IL-1β expression driven by androgen receptor absence or inactivation promotes prostate cancer bone metastasis
Anthony DiNatale1,2, Asurayya Worrede1,3, Waleed Iqbal4
1Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA.
Abstract:
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.
Insights
Androgen receptor (AR) normally represses interleukin-1beta (IL-1β) in prostate cancer. When AR is lost or inhibited, IL-1β can promote cancer metastasis by altering the tumor microenvironment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Prostate cancer progression involves complex molecular interactions.
- Androgen receptor (AR) signaling is a key driver in prostate cancer.
- Interleukin-1beta (IL-1β) is implicated in cancer metastasis.
Purpose of the Study:
- To investigate the relationship between AR and IL-1β expression in metastatic castration-resistant prostate cancer (mCRPC).
- To elucidate the mechanism by which AR regulates IL-1β.
- To understand the implications of IL-1β expression in AR-negative or treated prostate cancer.
Main Methods:
- Analysis of AR and IL-1β expression in mCRPC patient cohorts.
- In vitro and in vivo studies assessing IL-1β regulation by AR.
- Investigation of epigenetic modifications (histone deacetylation, DNA methylation) at the IL-1β promoter.
Main Results:
- An inverse association was found between AR and IL-1β expression.
- AR represses IL-1β gene expression via binding to an androgen response element.
- Androgen depletion or AR pathway inhibitors de-repressed IL-1β in AR-positive cells.
- Histone deacetylation (H3K27) and DNA methylation were identified as regulatory mechanisms.
- Secreted IL-1β was shown to support metastatic progression in preclinical models.
Conclusions:
- AR directly represses IL-1β transcription.
- Loss of AR signaling or inhibition leads to IL-1β de-repression.
- IL-1β can drive prostate cancer metastasis by modulating the bone stroma.
- Unmethylated IL-1β in AR-negative or treated mCRPC may sustain disease progression by conditioning the metastatic microenvironment.
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