Epigenetic reader ZMYND11 noncanonical function restricts HNRNPA1-mediated stress granule formation and oncogenic activity  

作　　者：Cheng Lian Chunyi Zhang Pan Tian Qilong Tan Yu Wei Zixian Wang Qin Zhang Qixiang Zhang Mengjie Zhong Li-Quan Zhou Xisong Ke Huabing Zhang Yao Zhu Zhenfei Li Jingdong Cheng Gong-Hong Wei 

机构地区：[1]Fudan University Shanghai Cancer Center&MOE Key Laboratory of Metabolism and Molecular Medicine and Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences,and Institutes of Biomedical Sciences,Shanghai Medical College,Fudan University,Shanghai,China [2]State Key Laboratory of Cell Biology,CAS Center for Excellence in Molecular Cell Science,Shanghai Institute of Biochemistry and Cell Biology,Chinese Academy of Sciences,University of Chinese Academy of Sciences,Shanghai,China [3]Department of Urology,Fudan University Shanghai Cancer Center,Shanghai,China [4]Disease Networks Research Unit,Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine,University of Oulu,Oulu,Finland [5]Institute of Reproductive Health,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei,China [6]Shanghai Frontiers Science Center of TCM Chemical Biology,Institute of Interdisciplinary Integrative Medicine Research,Shanghai University of Traditional Chinese Medicine,Shanghai,China [7]Department of Biochemistry and Molecular Biology,Metabolic Disease Research Center,School of Basic Medicine,Anhui Medical University,Hefei,China [8]Minhang Hospital&Institutes of Biomedical Sciences,Shanghai Key Laboratory of Medical Epigenetics,International Co-laboratory of Medical Epigenetics and Metabolism,Fudan University,Shanghai,China [9]State Key Laboratory of Common Mechanism Research for Major Diseases,Suzhou Institute of Systems Medicine,Chinese Academy of Medical Sciences&Peking Union Medical College,Suzhou,Jiangsu,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第10期4708-4729,共22页信号转导与靶向治疗（英文）

基　　金：National Key Research and Development Program of China(2022YFC2703600);National Natural Science Foundation of China(82073082,82311530050,81772948,81972617);Shanghai Interactional Collaborative Project(23410713300);Key Research and Development Program of Anhui Province(2022i01020023)。

摘　　要：Epigenetic readers frequently affect gene regulation,correlate with disease prognosis,and hold significant potential as therapeutic targets for cancer.Zinc finger MYND-type containing 11(ZMYND11)is notably recognized for reading the epigenetic marker H3.3K36me3;however,its broader functions and mechanisms of action in cancer remain underexplored.Here,we report that ZMYND11 downregulation is prevalent across various cancers and profoundly correlates with poorer outcomes in prostate cancer patients.Depletion of ZMYND11 promotes tumor cell growth,migration,and invasion in vitro,as well as tumor formation and metastasis in vivo.Mechanistically,we discover that ZMYND11 exhibits tumor suppressive roles by recognizing arginine-194-methylated HNRNPA1 dependent on its MYND domain,thereby retaining HNRNPA1 in the nucleus and preventing the formation of stress granules in the cytoplasm.Furthermore,ZMYND11 counteracts the HNRNPA1-driven increase in the PKM2/PKM1 ratio,thus mitigating the aggressive tumor phenotype promoted by PKM2.Remarkably,ZMYND11 recognition of HNRNPA1 can be disrupted by pharmaceutical inhibition of the arginine methyltransferase PRMT5.Tumors with low ZMYND11 expression show sensitivity to PRMT5 inhibitors.Taken together,our findings uncover a previously unexplored noncanonical role of ZMYND11 as a nonhistone methylation reader and underscore the critical importance of arginine methylation in the ZMYND11-HNRNPA1 interaction for restraining tumor progression,thereby proposing novel therapeutic targets and potential biomarkers for cancer treatment.

关 键 词：INVASION thereby stress 

分 类 号：R392.2[医药卫生—免疫学]