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Epigenetic reader ZMYND11 noncanonical function restricts HNRNPA1-mediated stress granule formation and oncogenic activity
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作者 Cheng Lian Chunyi Zhang +13 位作者 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 《Signal Transduction and Targeted Therapy》 SCIE CSCD 2024年第10期4708-4729,共22页
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 ... 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. 展开更多
关键词 INVASION thereby stress
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