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Updated: Jan 21, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
The androgen receptor regulates a druggable translational regulon in advanced prostate cancer
Yuzhen Liu1, Jessie L Horn1, Kalyan Banda1
1Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Abstract:
The androgen receptor (AR) is a driver of cellular differentiation and prostate cancer development. An extensive body of work has linked these normal and aberrant cellular processes to mRNA transcription; however, the extent to which AR regulates posttranscriptional gene regulation remains unknown. Here, we demonstrate that AR uses the translation machinery to shape the cellular proteome. We show that AR is a negative regulator of protein synthesis and identify an unexpected relationship between AR and the process of translation initiation in vivo. This is mediated through direct transcriptional control of the translation inhibitor 4EBP1. We demonstrate that lowering AR abundance increases the assembly of the eIF4F translation initiation complex, which drives enhanced tumor cell proliferation. Furthermore, we uncover a network of pro-proliferation mRNAs characterized by a guanine-rich cis-regulatory element that is particularly sensitive to eIF4F hyperactivity. Using both genetic and pharmacologic methods, we demonstrate that dissociation of the eIF4F complex reverses the proliferation program, resulting in decreased tumor growth and improved survival in preclinical models. Our findings reveal a druggable nexus that functionally links the processes of mRNA transcription and translation initiation in an emerging class of lethal AR-deficient prostate cancer.
Insights
Androgen receptor (AR) negatively regulates protein synthesis by controlling translation initiation. Targeting this pathway reduces tumor growth in preclinical models of lethal prostate cancer.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- The androgen receptor (AR) drives prostate cancer development and cellular differentiation.
- While AR's role in mRNA transcription is established, its regulation of posttranscriptional processes is unclear.
Purpose of the Study:
- To investigate AR's role in posttranscriptional gene regulation, specifically protein synthesis and translation initiation.
- To identify mechanisms linking AR to translation and its impact on prostate cancer proliferation.
Main Methods:
- Investigated AR's regulation of protein synthesis and translation initiation in vivo.
- Identified direct transcriptional control of 4EBP1 by AR.
- Analyzed AR's effect on the eIF4F translation initiation complex and pro-proliferation mRNAs.
- Utilized genetic and pharmacologic methods to target the eIF4F complex in preclinical models.
Main Results:
- AR acts as a negative regulator of protein synthesis by controlling translation initiation via 4EBP1.
- Reduced AR levels enhance eIF4F complex assembly, promoting tumor cell proliferation.
- A network of pro-proliferation mRNAs sensitive to eIF4F hyperactivity was identified.
- Dissociating the eIF4F complex reversed proliferation, decreasing tumor growth and improving survival.
Conclusions:
- AR functionally links mRNA transcription and translation initiation in AR-deficient prostate cancer.
- Targeting the eIF4F complex offers a potential therapeutic strategy for lethal prostate cancer.
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