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Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy

Author

Listed:
  • Wenjing Bai

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Jinxin Xu

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Wenbin Gu

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Danyang Wang

    (Chinese Academy of Sciences)

  • Ying Cui

    (The Johns Hopkins University School of Medicine)

  • Weidong Rong

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Xiaoan Du

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xiaoxia Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Cuicui Xia

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Qingqing Gan

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Guantao He

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Huahui Guo

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jinfeng Deng

    (Chinese Academy of Sciences)

  • Yuqiong Wu

    (Chinese Academy of Sciences)

  • Ray-Whay Chiu Yen

    (The Johns Hopkins University School of Medicine)

  • Srinivasan Yegnasubramanian

    (The Johns Hopkins University School of Medicine)

  • Scott B. Rothbart

    (Van Andel Institute)

  • Cheng Luo

    (Chinese Academy of Sciences
    Guizhou Medical University)

  • Linping Wu

    (Chinese Academy of Sciences)

  • Jinsong Liu

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Stephen B. Baylin

    (The Johns Hopkins University School of Medicine
    Van Andel Institute)

  • Xiangqian Kong

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    Chinese Academy of Sciences
    The Johns Hopkins University School of Medicine)

Abstract

UHRF1 maintains DNA methylation by recruiting DNA methyltransferases to chromatin. In mouse, these dynamics are potently antagonized by a natural UHRF1 inhibitory protein STELLA, while the comparable effects of its human ortholog are insufficiently characterized, especially in cancer cells. Herein, we demonstrate that human STELLA (hSTELLA) is inadequate, while mouse STELLA (mSTELLA) is fully proficient in inhibiting the abnormal DNA methylation and oncogenic functions of UHRF1 in human cancer cells. Structural studies reveal a region of low sequence homology between these STELLA orthologs that allows mSTELLA but not hSTELLA to bind tightly and cooperatively to the essential histone-binding, linked tandem Tudor domain and plant homeodomain (TTD-PHD) of UHRF1, thus mediating ortholog-specific UHRF1 inhibition. For translating these findings to cancer therapy, we use a lipid nanoparticle (LNP)-mediated mRNA delivery approach in which the short mSTELLA, but not hSTELLA regions are required to reverse cancer-specific DNA hypermethylation and impair colorectal cancer tumorigenicity.

Suggested Citation

  • Wenjing Bai & Jinxin Xu & Wenbin Gu & Danyang Wang & Ying Cui & Weidong Rong & Xiaoan Du & Xiaoxia Li & Cuicui Xia & Qingqing Gan & Guantao He & Huahui Guo & Jinfeng Deng & Yuqiong Wu & Ray-Whay Chiu , 2025. "Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55481-7
    DOI: 10.1038/s41467-024-55481-7
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