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The Transmembrane Protein TM4SF3 Interacts With AR and AR-V7 and is Recruited to AR Target Genes

Prabesh Khatiwada1, Ujjwal Rimal1, Zhengyang Han1

  • 1Department of Biological Sciences, University of Toledo, Toledo, OH 43606, USA.

Endocrinology
|March 23, 2023
PubMed

Insights

Transmembrane 4 superfamily 3 (TM4SF3) regulates androgen receptor (AR) and its variant AR-V7, crucial drivers of lethal castration-resistant prostate cancer (CRPC). TM4SF3 stabilizes AR/AR-V7 by deubiquitination and is essential for CRPC gene expression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Prostate cancer (PC) progresses to lethal castration-resistant prostate cancer (CRPC).
  • Androgen receptor (AR) and its splice variant AR-V7 are key drivers of CRPC.
  • TM4SF3 was previously identified as a novel AR regulator.

Purpose of the Study:

  • To elucidate the interaction domains between TM4SF3, AR, and AR-V7.
  • To investigate the role of TM4SF3 in regulating AR-V7 stability and CRPC cell viability.
  • To determine the impact of TM4SF3 on the transcriptional activity of AR and AR-V7.

Main Methods:

  • Protein interaction mapping of AR and TM4SF3.
  • Co-immunoprecipitation and Western blotting to assess protein stability and ubiquitination.
  • Immunofluorescence and chromatin immunoprecipitation assays to evaluate nuclear localization and gene regulation.

Main Results:

  • TM4SF3 interacts with both AR and AR-V7, regulating their protein stability through mutual deubiquitination.
  • TM4SF3 interaction with AR/AR-V7 enhances CRPC cell viability.
  • Nuclear TM4SF3 is recruited to AR/AR-V7 target gene promoters, facilitating their expression.

Conclusions:

  • TM4SF3 plays a critical, multifaceted role in regulating AR and AR-V7 in prostate cancer.
  • TM4SF3-mediated deubiquitination is a key mechanism for AR/AR-V7 stabilization.
  • TM4SF3 is essential for the transcriptional function of AR/AR-V7, highlighting its potential as a therapeutic target in CRPC.
Keywords:
ARAR-V7TM4SF3prostate cancer

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