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Posttranslational regulation of FOXA1 by Polycomb and BUB3/USP7 deubiquitin complex in prostate cancer

Su H Park1, Ka-Wing Fong1, Jung Kim1,2

  • 1Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Science Advances
|April 8, 2021
PubMed

Insights

Researchers discovered enhancer of zeste homolog 2 (EZH2) methylates Forkhead box protein A1 (FOXA1), stabilizing it and promoting prostate cancer (PCa) growth. This finding offers new therapeutic strategies targeting EZH2 and USP7 for PCa treatment.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • Forkhead box protein A1 (FOXA1) is crucial for prostate cancer (PCa) progression.
  • Mechanisms regulating FOXA1 protein levels and its therapeutic targeting in PCa are not fully understood.

Purpose of the Study:

  • To elucidate the regulatory mechanisms governing FOXA1 protein stability.
  • To investigate the role of FOXA1 regulation in prostate cancer growth.
  • To explore potential therapeutic strategies targeting FOXA1 stability in PCa.

Main Methods:

  • Identified FOXA1 as a nonhistone substrate of enhancer of zeste homolog 2 (EZH2).
  • Investigated the role of EZH2-mediated methylation at lysine-295 of FOXA1.
  • Examined the interaction of methylated FOXA1 with WD40 repeat protein BUB3 and ubiquitin-specific protease 7 (USP7).

Main Results:

  • EZH2 methylates FOXA1 at lysine-295, enhancing its protein stability via BUB3 and USP7.
  • This regulatory axis (EZH2-FOXA1-BUB3-USP7) controls cell cycle genes and promotes PCa growth.
  • Inhibitors targeting EZH2 methyltransferase activity mitigate FOXA1-driven PCa growth.

Conclusions:

  • EZH2-catalyzed methylation is a key mechanism for FOXA1 protein stabilization in prostate cancer.
  • Targeting EZH2 enzymatic activity, alone or with USP7 inhibitors, shows therapeutic potential for PCa.
  • Understanding this regulatory pathway provides novel avenues for PCa treatment strategies.

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