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Mi-2β promotes immune evasion in melanoma by activating EZH2 methylation

Author

Listed:
  • Cang Li

    (Zhejiang University
    Binjiang Institute of Zhejiang University)

  • Zhengyu Wang

    (University of Arkansas for Medical Science)

  • Licheng Yao

    (Tsinghua University)

  • Xingyu Lin

    (Zhuhai Yu Fan Biotechnologies Co. Ltd)

  • Yongping Jian

    (Henan University)

  • Yujia Li

    (Henan University)

  • Jie Zhang

    (Nanjing University)

  • Jingwei Shao

    (Chongqing University of Arts and Sciences)

  • Phuc D. Tran

    (University of Arkansas for Medical Science)

  • James R. Hagman

    (National Jewish Health)

  • Meng Cao

    (Nanjing University of Chinese Medicine)

  • Yusheng Cong

    (Hangzhou Normal University School of Basic Medical Sciences)

  • Hong-yu Li

    (University of Arkansas for Medical Science)

  • Colin R. Goding

    (University of Oxford, Headington)

  • Zhi-Xiang Xu

    (Henan University)

  • Xuebin Liao

    (Tsinghua University)

  • Xiao Miao

    (Shanghai University of Traditional Chinese Medicine
    Jiangxi Medical College, Nanchang University)

  • Rutao Cui

    (Zhejiang University)

Abstract

Recent development of new immune checkpoint inhibitors has been particularly successfully in cancer treatment, but still the majority patients fail to benefit. Converting resistant tumors to immunotherapy sensitive will provide a significant improvement in patient outcome. Here we identify Mi-2β as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Studies in genetically engineered mouse melanoma models indicate that loss of Mi-2β rescues the immune response to immunotherapy in vivo. Mechanistically, ATAC-seq analysis shows that Mi-2β controls the accessibility of IFN-γ-stimulated genes (ISGs). Mi-2β binds to EZH2 and promotes K510 methylation of EZH2, subsequently activating the trimethylation of H3K27 to inhibit the transcription of ISGs. Finally, we develop an Mi-2β-targeted inhibitor, Z36-MP5, which reduces Mi-2β ATPase activity and reactivates ISG transcription. Consequently, Z36-MP5 induces a response to immune checkpoint inhibitors in otherwise resistant melanoma models. Our work provides a potential therapeutic strategy to convert immunotherapy resistant melanomas to sensitive ones.

Suggested Citation

  • Cang Li & Zhengyu Wang & Licheng Yao & Xingyu Lin & Yongping Jian & Yujia Li & Jie Zhang & Jingwei Shao & Phuc D. Tran & James R. Hagman & Meng Cao & Yusheng Cong & Hong-yu Li & Colin R. Goding & Zhi-, 2024. "Mi-2β promotes immune evasion in melanoma by activating EZH2 methylation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46422-5
    DOI: 10.1038/s41467-024-46422-5
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