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

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-Xiang Xu (), Xuebin Liao (), Xiao Miao () and Rutao Cui ()
Additional contact information
Cang Li: 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
Rutao Cui: Zhejiang University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46422-5

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