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Phosphorylation and stabilization of EZH2 by DCAF1/VprBP trigger aberrant gene silencing in colon cancer

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Listed:
  • Nikhil B. Ghate

    (University of Southern California)

  • Sungmin Kim

    (University of Southern California)

  • Yonghwan Shin

    (University of Southern California)

  • Jinman Kim

    (University of Southern California)

  • Michael Doche

    (University of Southern California)

  • Scott Valena

    (University of Southern California)

  • Alan Situ

    (University of Southern California)

  • Sangnam Kim

    (University of Southern California)

  • Suhn K. Rhie

    (University of Southern California)

  • Heinz-Josef Lenz

    (University of Southern California)

  • Tobias S. Ulmer

    (University of Southern California)

  • Shannon M. Mumenthaler

    (University of Southern California)

  • Woojin An

    (University of Southern California)

Abstract

Our recent work has shown that DCAF1 (also known as VprBP) is overexpressed in colon cancer and phosphorylates histone H2AT120 to drive epigenetic gene inactivation and oncogenic transformation. We have extended these observations by investigating whether DCAF1 also phosphorylates non-histone proteins as an additional mechanism linking its kinase activity to colon cancer development. We now demonstrate that DCAF1 phosphorylates EZH2 at T367 to augment its nuclear stabilization and enzymatic activity in colon cancer cells. Consistent with this mechanistic role, DCAF1-mediated EZH2 phosphorylation leads to elevated levels of H3K27me3 and altered expression of growth regulatory genes in cancer cells. Furthermore, our preclinical studies using organoid and xenograft models revealed that EZH2 requires phosphorylation for its oncogenic function, which may have therapeutic implications for gene reactivation in colon cancer cells. Together, our data define a mechanism underlying DCAF1-driven colonic tumorigenesis by linking DCAF1-mediated EZH2 phosphorylation to EZH2 stability that is crucial for establishing H3K27me3 and gene silencing program.

Suggested Citation

  • Nikhil B. Ghate & Sungmin Kim & Yonghwan Shin & Jinman Kim & Michael Doche & Scott Valena & Alan Situ & Sangnam Kim & Suhn K. Rhie & Heinz-Josef Lenz & Tobias S. Ulmer & Shannon M. Mumenthaler & Wooji, 2023. "Phosphorylation and stabilization of EZH2 by DCAF1/VprBP trigger aberrant gene silencing in colon cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37883-1
    DOI: 10.1038/s41467-023-37883-1
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    References listed on IDEAS

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    1. Xiaobei Zhao & Eivind Valen & Brian J Parker & Albin Sandelin, 2011. "Systematic Clustering of Transcription Start Site Landscapes," PLOS ONE, Public Library of Science, vol. 6(8), pages 1-16, August.
    2. Raphaël Margueron & Danny Reinberg, 2011. "The Polycomb complex PRC2 and its mark in life," Nature, Nature, vol. 469(7330), pages 343-349, January.
    3. Talha Anwar & Caroline Arellano-Garcia & James Ropa & Yu-Chih Chen & Hong Sun Kim & Euisik Yoon & Sierrah Grigsby & Venkatesha Basrur & Alexey I. Nesvizhskii & Andrew Muntean & Maria E. Gonzalez & Kel, 2018. "p38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
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