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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

Published on: March 6, 2018

BRD4 Regulates Metastatic Potential of Castration-Resistant Prostate Cancer through AHNAK

Jordan S Shafran^1,2, Guillaume P Andrieu¹, Balázs Györffy^3,4

¹Boston University-Boston Medical Center Cancer Center, Boston, Massachusetts.

Molecular Cancer Research : MCR

|May 22, 2019

Abstract:

The inevitable progression of advanced prostate cancer to castration resistance, and ultimately to lethal metastatic disease, depends on primary or acquired resistance to conventional androgen deprivation therapy (ADT) and accumulated resistance strategies to evade androgen receptor (AR) suppression. In prostate cancer cells, AR adaptations that arise in response to ADT are not singular, but diverse, and include gene amplification, mutation, and even complete loss of receptor expression. Collectively, each of these AR adaptations contributes to a complex, heterogeneous, ADT-resistant tumor. Here, we examined prostate cancer cell lines that model common castration-resistant prostate cancer (CRPC) subtypes, each with different AR composition, and focused on novel regulators of tumor progression, the Bromodomain and Extraterminal (BET) family of proteins. We found that BRD4 regulates cell migration across all models of CRPC, regardless of aggressiveness and AR status, whereas BRD2 and BRD3 only regulate migration and invasion in less aggressive models that retain AR expression or signaling. BRD4, a coregulator of gene transcription, controls migration and invasion through transcription of AHNAK, a large scaffolding protein linked to promotion of metastasis in a diverse set of cancers. Furthermore, treatment of CRPC cell lines with low doses of MZ1, a small-molecule, BRD4-selective degrader, inhibits metastatic potential. Overall, these results reveal a novel BRD4-AHNAK pathway that may be targetable to treat metastatic CRPC (mCRPC). IMPLICATIONS: BRD4 functions as the dominant regulator of CRPC cell migration and invasion through direct transcriptional regulation of AHNAK, which together offer a novel targetable pathway to treat metastatic CRPC.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/8/1627/F1.large.jpg.

Insights

Bromodomain and Extraterminal (BET) proteins, particularly BRD4, drive prostate cancer metastasis by regulating AHNAK. Targeting BRD4 with MZ1 inhibits this progression, offering a new therapeutic strategy for metastatic castration-resistant prostate cancer (mCRPC).

Area of Science:

Oncology
Molecular Biology
Cancer Research

Background:

Advanced prostate cancer often progresses to castration-resistant prostate cancer (CRPC) despite androgen deprivation therapy (ADT).
Tumor cells develop diverse resistance strategies, including androgen receptor (AR) adaptations, leading to heterogeneous and aggressive disease.
Bromodomain and Extraterminal (BET) proteins are emerging as key regulators in various cancers.

Purpose of the Study:

To investigate the role of BET proteins, specifically BRD4, BRD2, and BRD3, in regulating cell migration and invasion across different subtypes of castration-resistant prostate cancer (CRPC).
To identify novel molecular pathways driving metastasis in CRPC.
To evaluate the therapeutic potential of targeting BRD4 in metastatic CRPC (mCRPC).

Main Methods:

Utilized CRPC cell line models representing diverse AR compositions and aggressiveness.
Assessed the regulatory roles of BRD4, BRD2, and BRD3 in cell migration and invasion.
Investigated the transcriptional targets of BRD4, focusing on AHNAK.
Treated CRPC cells with MZ1, a selective BRD4 degrader, to assess its impact on metastatic potential.

Main Results:

BRD4 was identified as a universal regulator of cell migration in all CRPC models, irrespective of AR status or aggressiveness.
BRD2 and BRD3 primarily influenced migration in less aggressive CRPC models with retained AR signaling.
BRD4 controls migration and invasion via transcriptional regulation of the scaffolding protein AHNAK.
Treatment with the BRD4 degrader MZ1 significantly inhibited the metastatic potential of CRPC cells.

Conclusions:

BRD4 is a dominant regulator of CRPC cell migration and invasion, acting through the AHNAK pathway.
The BRD4-AHNAK axis represents a novel and targetable pathway for treating metastatic CRPC (mCRPC).
Targeting BRD4 offers a promising therapeutic strategy to combat prostate cancer metastasis.

Read full analysis

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