2. Academic Validation
  3. Mi-2β promotes immune evasion in melanoma by activating EZH2 methylation

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

  • Nat Commun. 2024 Mar 9;15(1):2163. doi: 10.1038/s41467-024-46422-5.
Cang Li # 1 2,  Zhengyu Wang # 3,  Licheng Yao # 4,  Xingyu Lin 5,  Yongping Jian 6,  Yujia Li 6,  Jie Zhang 7,  Jingwei Shao 8,  Phuc D Tran 3,  James R Hagman 9,  Meng Cao 10,  Yusheng Cong 11,  Hong-Yu Li 12,  Colin R Goding 13,  Zhi-Xiang Xu 14,  Xuebin Liao 15,  Xiao Miao 16 17,  Rutao Cui 18
Affiliations

Affiliations

  • 1 Skin Disease Research Institute, The 2nd Hospital and School of Medicine, Zhejiang University, Hangzhou, 310058, China.
  • 2 Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou, 310053, China.
  • 3 Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Science, Little Rock, AR, 72205, USA.
  • 4 State Key Laboratory of Molecular Oncology, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Science, Tsinghua University, Beijing, 100084, China.
  • 5 Zhuhai Yu Fan Biotechnologies Co. Ltd, Zhuhai, Guangdong, 51900, China.
  • 6 School of Life Sciences, Henan University, Kaifeng, 475000, China.
  • 7 National Key Laboratory for Novel Software Technology, Nanjing University, Nanjing, Jiangsu, China.
  • 8 National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, International Academy of Targeted Therapeutics and Innovation, College of Pharmacy, Chongqing University of Arts and Sciences, Chongqing, 402160, China.
  • 9 Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO, 80206, USA.
  • 10 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 11 Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Hangzhou Normal University School of Basic Medical Sciences, Hangzhou, 310058, China.
  • 12 Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Science, Little Rock, AR, 72205, USA. lih1@uthscsa.edu.
  • 13 Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford, OX3 7DQ, UK. colin.goding@ludwig.ox.ac.uk.
  • 14 School of Life Sciences, Henan University, Kaifeng, 475000, China. 10140187@vip.henu.edu.cn.
  • 15 State Key Laboratory of Molecular Oncology, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Science, Tsinghua University, Beijing, 100084, China. liaoxuebin@mail.tsinghua.edu.cn.
  • 16 Department of Dermatology, Shuguang Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China. 0000002623@shutcm.edu.cn.
  • 17 The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Jiangxi Medical College, Nanchang University, Nanchang, China. 0000002623@shutcm.edu.cn.
  • 18 Skin Disease Research Institute, The 2nd Hospital and School of Medicine, Zhejiang University, Hangzhou, 310058, China. rutaocui@zju.edu.cn.
  • # Contributed equally.
PMID: 38461299 DOI: 10.1038/s41467-024-46422-5
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-161344
    Mi-2β-targeted 抑制剂
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