表观遗传解读器经常影响基因调控，与疾病预后相关，并具有作为癌症治疗靶点的巨大潜力。含有 11 (ZMYND11) 的锌指 MYND 型因读取表观遗传标记 H3.3K36me3 而被特别识别；然而，其更广泛的功能和在癌症中的作用机制仍未得到充分探索。在此，我们报告 ZMYND11 下调在各种癌症中普遍存在，并且与前列腺癌患者较差的预后密切相关。 ZMYND11 的缺失可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。从机制上讲，我们发现ZMYND11通过依赖其MYND结构域识别精氨酸-194-甲基化的HNRNPA1来发挥肿瘤抑制作用，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 HNRNPA1 驱动的 PKM2/PKM1 比率的增加，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 的识别可以通过药物抑制精氨酸甲基转移酶 PRMT5 来破坏。 ZMYND11 低表达的肿瘤对 PRMT5 抑制剂表现出敏感性。总而言之，我们的研究结果揭示了 ZMYND11 作为非组蛋白甲基化读取器的先前未探索的非典型作用，并强调了精氨酸甲基化在 ZMYND11-HNRNPA1 相互作用中对于抑制肿瘤进展的至关重要性，从而为癌症治疗提出了新的治疗靶点和潜在的生物标志物。© 2024。作者。

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.© 2024. The Author(s).