表观遗传学读取器ZMYND11非规范功能限制HNRNPA1介导的应激颗粒形成和致癌活性
Epigenetic reader ZMYND11 noncanonical function restricts HNRNPA1-mediated stress granule formation and oncogenic activity
影响因子:52.70000
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
摘要
表观遗传学读者经常影响基因调节，与疾病预后相关，并具有巨大的潜力作为癌症的治疗靶标。含有11（Zmynd11）的锌指mynd型因读取表观遗传标记H3.3K36me3而被认可。但是，其在癌症中的更广泛的功能和作用机制仍然没有得到充实的态度。在这里，我们报告说，Zmynd11的下调在各种癌症中普遍存在，并且与前列腺癌患者的预后较差有关。 Zmynd11的耗竭促进体外肿瘤细胞的生长，迁移和侵袭，以及体内肿瘤的形成和转移。从机械上讲，我们发现ZMYND11通过识别精氨酸194-甲基化的HNRNPA1来表现出肿瘤抑制作用，从而依赖于其MYND结构域，从而将HNRNPA1保留在细胞核中并防止细胞质中应激颗粒的形成。此外，Zmynd11抵消了PKM2/PKM1比的HNRNPA1驱动的增加，从而减轻了PKM2促进的侵袭性肿瘤表型。值得注意的是，ZMYND11对HNRNPA1的识别可能会因精氨酸甲基转移酶PRMT5的药物抑制而破坏。 ZMYND11表达较低的肿瘤对PRMT5抑制剂的敏感性。综上所述，我们的发现发现了Zmynd11作为非组蛋白甲基化读剂的先前未探索的非环境作用，并强调了精氨酸甲基化在ZMYND11-HNRNPA1相互作用中对抑制肿瘤进展的至关重要的重要性，从而提出了新的治疗靶标和潜在的生物标志物来治疗癌症治疗。
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.