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, Rutao Cui

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number2163
JournalNature communications
Issue number1
StatePublished - Dec 2024
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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