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

• Published in: Signal transduction and targeted therapy 2024-09, Vol.9 (1), p.258-22, Article 258
• Main Authors: Lian, Cheng, Zhang, Chunyi, Tian, Pan, Tan, Qilong, Wei, Yu, Wang, Zixian, Zhang, Qin, Zhang, Qixiang, Zhong, Mengjie, Zhou, Li-Quan, Ke, Xisong, Zhang, Huabing, Zhu, Yao, Li, Zhenfei, Cheng, Jingdong, Wei, Gong-Hong
• Format: Article
• Language: English
• Subjects: 631/67/68; 692/699/67/395; Animals; Arginine; Cancer; Cancer Research; Cancer therapies; Carcinogenesis - genetics; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Biology; Cell Cycle Proteins; Cell Line, Tumor; Cell migration; Co-Repressor Proteins; Cytoplasm; DNA-Binding Proteins; Epigenesis, Genetic - genetics; Epigenetics; Gene Expression Regulation, Neoplastic - genetics; Gene regulation; Heterogeneous Nuclear Ribonucleoprotein A1 - genetics; Heterogeneous Nuclear Ribonucleoprotein A1 - metabolism; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Metastases; Mice; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Oncology; Pathology; Phenotypes; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein arginine methyltransferase; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; Stress Granules - genetics; Stress Granules - metabolism; Therapeutic targets; Tumors; Zinc finger proteins
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-024-01961-7

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.