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Updated: Aug 2, 2025

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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Phosphorylation and stabilization of EZH2 by DCAF1/VprBP trigger aberrant gene silencing in colon cancer

Nikhil B Ghate1, Sungmin Kim1, Yonghwan Shin1

  • 1Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA.

Nature Communications
|April 17, 2023
PubMed

Insights

DCAF1 protein promotes colon cancer by phosphorylating EZH2, increasing its stability and gene-silencing activity. This finding offers potential therapeutic strategies for colon cancer by targeting EZH2 reactivation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • DCAF1 (VprBP) is overexpressed in colon cancer, where it drives oncogenesis via histone phosphorylation.
  • The role of DCAF1 in phosphorylating non-histone proteins in colon cancer remains unexplored.

Purpose of the Study:

  • To investigate if DCAF1 phosphorylates non-histone proteins in colon cancer.
  • To elucidate the mechanism by which DCAF1 influences colon cancer development through non-histone protein phosphorylation.

Main Methods:

  • Western blotting and immunoprecipitation to detect protein phosphorylation.
  • Quantitative PCR and RNA sequencing to analyze gene expression.
  • Organoid and xenograft models for preclinical validation.

Main Results:

  • DCAF1 phosphorylates EZH2 at threonine 367 (T367) in colon cancer cells.
  • Phosphorylation enhances EZH2's nuclear stability and enzymatic activity.
  • DCAF1-mediated EZH2 phosphorylation increases H3K27me3 levels and alters growth-regulatory gene expression.
  • Preclinical models confirm EZH2 phosphorylation is essential for its oncogenic function.

Conclusions:

  • DCAF1-mediated EZH2 phosphorylation stabilizes EZH2, promoting H3K27me3 and gene silencing in colon cancer.
  • This mechanism highlights a novel pathway in DCAF1-driven tumorigenesis.
  • Targeting EZH2 phosphorylation presents a potential therapeutic strategy for colon cancer gene reactivation.

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