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Updated: Apr 19, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
BET bromodomain inhibitors--a novel epigenetic approach in castration-resistant prostate cancer
Sarah E Lochrin1, Douglas K Price, William D Figg
1a Genitourinary Malignancies Branch; Center for Cancer Research; National Cancer Institute ; Bethesda , MD USA.
Abstract:
The androgen receptor (AR) is central to the initiation and progression of prostate cancer, even after castration. There has been some success in therapies targeting AR signaling which have been shown to extend survival in men with castration-resistant prostate cancer (CRPC). However, durable responses to these therapies have been limited and there is a need to identify additional therapeutic targets within the AR-signaling network. Recently a group at University of Michigan Medical School outlined the potential for BET bromodomain protein inhibitors as a novel epigenetic approach to treatment of CRPC. In prostate cancer cell lines, BET bromodomain inhibitor, JQ1, was shown to induce apoptosis and down-regulate AR-regulated gene transcription. Bromodomain and the extra-terminal (BET) subfamily of human bromodomain proteins, with a focus on BRD4, were shown to play a major role in AR signaling and interact with AR via bromodomain (BD) 1/2. JQ1 inhibits this BRD4-AR bond, resulting in removal of RNA polymerase II from AR target genes, causing reduced AR gene transcription and subsequent diminished AR signaling. JQ1 lead to a significant reduction in tumor volume and weight in VCaP xenograft mice.
Insights
BET bromodomain inhibitors, like JQ1, show promise for treating castration-resistant prostate cancer (CRPC). JQ1 targets the interaction between BRD4 and the androgen receptor (AR), reducing AR signaling and tumor growth.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Androgen receptor (AR) signaling drives prostate cancer progression, including castration-resistant prostate cancer (CRPC).
- Current therapies targeting AR signaling offer limited durable responses, necessitating novel therapeutic strategies.
- BET bromodomain proteins, particularly BRD4, are implicated in AR signaling pathways.
Purpose of the Study:
- To investigate BET bromodomain inhibitors as a novel epigenetic approach for CRPC treatment.
- To evaluate the efficacy of the BET bromodomain inhibitor JQ1 in preclinical models of prostate cancer.
Main Methods:
- Utilized prostate cancer cell lines and VCaP xenograft mouse models.
- Administered BET bromodomain inhibitor JQ1.
- Assessed apoptosis, AR-regulated gene transcription, and tumor volume/weight.
Main Results:
- JQ1 induced apoptosis and down-regulated AR-regulated gene transcription in prostate cancer cell lines.
- JQ1 inhibited the interaction between BRD4 and AR, leading to reduced RNA polymerase II recruitment to AR target genes.
- JQ1 significantly reduced tumor volume and weight in VCaP xenograft mice.
Conclusions:
- BET bromodomain inhibition represents a potential epigenetic therapy for CRPC.
- Targeting the BRD4-AR interaction with JQ1 effectively diminishes AR signaling and suppresses tumor growth.
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