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NEDD4L represses prostate cancer cell proliferation via modulating PHF8 through the ubiquitin-proteasome pathway

Rui Feng1,2, Zhongxing Li2, Guangcheng Ge2

  • 1Department of Urology, The First Affiliated Hospital of Soochow University, No. 188 Shizi Road, Suzhou, 215006, Jiangsu Province, People's Republic of China.

Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico
|September 22, 2022
PubMed
Abstract

Insights

Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) suppresses prostate cancer cell proliferation by targeting PHF8 for degradation, which limits ATF2 transcription. This mechanism highlights NEDD4L as a potential therapeutic target for prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Prostate cancer (PC) is a significant health concern globally.
  • E3 ubiquitin-protein ligase NEDD4L plays a role in various cancers.
  • Understanding NEDD4L's mechanism in PC is crucial for therapeutic development.

Purpose of the Study:

  • To investigate the role of NEDD4L in prostate cancer cell proliferation.
  • To elucidate the mechanism by which NEDD4L regulates PHF8 and ATF2.
  • To explore the involvement of the ubiquitin-proteasome system in this regulation.

Main Methods:

  • Quantitative PCR and Western blotting to assess expression levels of NEDD4L, PHF8, H3K9me2, and ATF2.
  • Cell proliferation assays (CCK-8, EdU) to evaluate the impact of NEDD4L, PHF8, and ATF2.
  • Co-immunoprecipitation and ubiquitination assays to determine protein interactions and modification.
  • Chromatin immunoprecipitation to analyze histone modifications and transcription factor binding.

Main Results:

  • NEDD4L was downregulated, while PHF8 and ATF2 were upregulated in PC tissues and cells.
  • NEDD4L overexpression inhibited prostate cancer cell proliferation.
  • NEDD4L induced PHF8 ubiquitination and degradation, subsequently reducing H3K9me2 enrichment at the ATF2 promoter and limiting ATF2 transcription.
  • Overexpression of PHF8 or ATF2 counteracted the inhibitory effect of NEDD4L on proliferation.

Conclusions:

  • NEDD4L suppresses prostate cancer cell proliferation by promoting PHF8 degradation.
  • This degradation leads to reduced ATF2 transcription, thereby inhibiting cancer cell growth.
  • NEDD4L-mediated regulation of PHF8 and ATF2 presents a potential therapeutic strategy for prostate cancer.
Keywords:
ATF2NEDD4LPHF8Prostate cancerUbiquitin–proteasome system

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