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Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity

Author

Listed:
  • Hanhan Ning

    (Tianjin Medical University)

  • Shan Huang

    (Tianjin Medical University)

  • Yang Lei

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Renyong Zhi

    (Tianjin Medical University)

  • Han Yan

    (Tianjin Medical University)

  • Jiaxing Jin

    (Tianjin Medical University)

  • Zhenyu Hu

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Kaimin Guo

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Jinhua Liu

    (Tianjin Medical University)

  • Jie Yang

    (Tianjin Medical University)

  • Zhe Liu

    (Tianjin Medical University)

  • Yi Ba

    (Tianjin Medical University Cancer Institute and Hospital)

  • Xin Gao

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Deqing Hu

    (Tianjin Medical University
    Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Medical University Cancer Institute and Hospital)

Abstract

Enhancer deregulation is a well-established pro-tumorigenic mechanism but whether it plays a regulatory role in tumor immunity is largely unknown. Here, we demonstrate that tumor cell ablation of mixed-lineage leukemia 3 and 4 (MLL3 and MLL4, also known as KMT2C and KMT2D, respectively), two enhancer-associated histone H3 lysine 4 (H3K4) mono-methyltransferases, increases tumor immunogenicity and promotes anti-tumor T cell response. Mechanistically, MLL4 ablation attenuates the expression of RNA-induced silencing complex (RISC) and DNA methyltransferases through decommissioning enhancers/super-enhancers, which consequently lead to transcriptional reactivation of the double-stranded RNA (dsRNA)-interferon response and gasdermin D (GSDMD)-mediated pyroptosis, respectively. More importantly, we reveal that both the dsRNA-interferon signaling and GSDMD-mediated pyroptosis are of critical importance to the increased anti-tumor immunity and improved immunotherapeutic efficacy in MLL4-ablated tumors. Thus, our findings establish tumor cell enhancers as an additional layer of immune evasion mechanisms and suggest the potential of targeting enhancers or their upstream and/or downstream molecular pathways to overcome immunotherapeutic resistance in cancer patients.

Suggested Citation

  • Hanhan Ning & Shan Huang & Yang Lei & Renyong Zhi & Han Yan & Jiaxing Jin & Zhenyu Hu & Kaimin Guo & Jinhua Liu & Jie Yang & Zhe Liu & Yi Ba & Xin Gao & Deqing Hu, 2022. "Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34253-1
    DOI: 10.1038/s41467-022-34253-1
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