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

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机构： [1]Skin Disease Research Institute, The 2nd Hospital and School of Medicine, Zhejiang University, Hangzhou 310058, China [2]Research Center for Life Scienceand 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.L td, 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 TargetedTherapeutics and Innovation, College of Pharmacy, Chongqing University of Arts and Sciences, Chongqing 402160, China [9]Department of Immunology andGenomic Medicine, National Jewish Health, Denver, CO 80206, USA [10]Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School ofPharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China [11]Key Laboratory of Aging and Cancer Biology of Zhejiang Province, HangzhouNormal University School of Basic Medical Sciences, Hangzhou 310058, China [12]Ludwig Institute for Cancer Research, Nuffield Department of ClinicalMedicine, University of Oxford, Headington, Oxford OX3 7DQ, UK [13]Department of Dermatology, Shuguang Hospital of Traditional Chinese Medicine,Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China [14]The MOE Basic Research and Innovation Center for the Targeted Therapeuticsof Solid Tumors, Jiangxi Medical College, Nanchang University, Nanchang, China

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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.© 2024. The Author(s).

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出版当年[2023]版：

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第一作者：

第一作者机构： [1]Skin Disease Research Institute, The 2nd Hospital and School of Medicine, Zhejiang University, Hangzhou 310058, China [2]Research Center for Life Scienceand Human Health, Binjiang Institute of Zhejiang University, Hangzhou 310053, China

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通讯机构： [13]Department of Dermatology, Shuguang Hospital of Traditional Chinese Medicine,Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China [14]The MOE Basic Research and Innovation Center for the Targeted Therapeuticsof Solid Tumors, Jiangxi Medical College, Nanchang University, Nanchang, China

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