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Prion-like domain mediated phase separation of ARID1A promotes oncogenic potential of Ewing’s sarcoma

Author

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  • Yong Ryoul Kim

    (Seoul National University)

  • Jaegeon Joo

    (Korea Advanced Institute of Science & Technology)

  • Hee Jung Lee

    (Seoul National University)

  • Chaelim Kim

    (Seoul National University)

  • Ju-Chan Park

    (Seoul National University College of Medicine
    Seoul National University College of Medicine)

  • Young Suk Yu

    (Seoul National University)

  • Chang Rok Kim

    (Seoul National University)

  • Do Hui Lee

    (Seoul National University)

  • Joowon Cha

    (Seoul National University)

  • Hyemin Kwon

    (Seoul National University)

  • Kimberley M. Hanssen

    (Hopp-Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK)
    National Center for Tumor Diseases (NCT), NCT Heidelberg, (A Partnership) Between DKFZ and Heidelberg University Hospital)

  • Thomas G. P. Grünewald

    (Hopp-Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK)
    National Center for Tumor Diseases (NCT), NCT Heidelberg, (A Partnership) Between DKFZ and Heidelberg University Hospital
    Heidelberg University Hospital)

  • Murim Choi

    (Seoul National University College of Medicine)

  • Ilkyu Han

    (Seoul National University College of Medicine)

  • Sangsu Bae

    (Seoul National University College of Medicine
    Seoul National University College of Medicine)

  • Inkyung Jung

    (Korea Advanced Institute of Science & Technology)

  • Yongdae Shin

    (Seoul National University
    Seoul National University)

  • Sung Hee Baek

    (Seoul National University)

Abstract

Liquid-liquid phase separation (LLPS) facilitates the formation of membraneless organelles within cells, with implications in various biological processes and disease states. AT-rich interactive domain-containing protein 1A (ARID1A) is a chromatin remodeling factor frequently associated with cancer mutations, yet its functional mechanism remains largely unknown. Here, we find that ARID1A harbors a prion-like domain (PrLD), which facilitates the formation of liquid condensates through PrLD-mediated LLPS. The nuclear condensates formed by ARID1A LLPS are significantly elevated in Ewing’s sarcoma patient specimen. Disruption of ARID1A LLPS results in diminished proliferative and invasive abilities in Ewing’s sarcoma cells. Through genome-wide chromatin structure and transcription profiling, we identify that the ARID1A condensate localizes to EWS/FLI1 target enhancers and induces long-range chromatin architectural changes by forming functional chromatin remodeling hubs at oncogenic target genes. Collectively, our findings demonstrate that ARID1A promotes oncogenic potential through PrLD-mediated LLPS, offering a potential therapeutic approach for treating Ewing’s sarcoma.

Suggested Citation

  • Yong Ryoul Kim & Jaegeon Joo & Hee Jung Lee & Chaelim Kim & Ju-Chan Park & Young Suk Yu & Chang Rok Kim & Do Hui Lee & Joowon Cha & Hyemin Kwon & Kimberley M. Hanssen & Thomas G. P. Grünewald & Murim , 2024. "Prion-like domain mediated phase separation of ARID1A promotes oncogenic potential of Ewing’s sarcoma," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51050-0
    DOI: 10.1038/s41467-024-51050-0
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