表观遗传阅读器ZMYND11的非经典功能限制HNRNPA1介导的应激颗粒形成及致癌活性

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

Signal Transduction and Targeted Therapy

影响因子:52.7

分区:医学1区 Top / 生化与分子生物学1区细胞生物学1区

发表日期:2024 Sep 28

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

DOI: 10.1038/s41392-024-01961-7

摘要

表观遗传阅读器常常影响基因调控，与疾病预后相关，并具有作为癌症治疗靶点的重大潜力。锌指MYND型蛋白ZMYND11以识读表观遗传标记H3.3K36me3而著称；然而，其在癌症中的更广泛功能及作用机制仍未被充分研究。在本研究中，我们发现ZMYND11在多种癌症中普遍下调，并且与前列腺癌患者预后较差显著相关。ZMYND11的耗竭促进体外肿瘤细胞的生长、迁移和侵袭，以及体内肿瘤形成和转移。机制上，我们发现ZMYND11通过其MYND结构域识别ARG-194甲基化的HNRNPA1，从而发挥肿瘤抑制作用，促使HNRNPA1留在细胞核中，防止其在细胞质中形成应激颗粒。此外，ZMYND11还可抵抗HNRNPA1驱动的PKM2/PKM1比率升高，从而减缓PKM2促进的肿瘤侵袭表型。值得注意的是，药理抑制精氨酸甲基转移酶PRMT5可以破坏ZMYND11对HNRNPA1的识别。低ZMYND11表达的肿瘤对PRMT5抑制剂表现出更高的敏感性。综上所述，我们揭示了ZMYND11作为非组蛋白甲基化读者的一个未被探索的非经典作用，强调了精氨酸甲基化在ZMYND11-HNRNPA1相互作用中抑制肿瘤进展的关键作用，为癌症治疗提出了新的潜在靶点和生物标志物。

Abstract

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.