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

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 () and Deqing Hu ()
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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

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34253-1

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