ZMYND8, an epigenetic regulator, was identified as a common oncogene across various tumors. However, little was reported about the association between ZMYND8 and bladder cancer. Besides, aberrant mechanisms that contribute to abnormal ZMYND8 expressions still remain unclear. In the current study, we first found that ZMYND8 protein levels were significantly elevated in Bca samples versus normal tissues, but not the mRNA levels. We then utilized the Cell Counting Kit-8 (CCK-8) assay, clone formation assay and transwell analysis to confirm that ZMYND8 could remarkably promote the tumor progression in vitro, including growth capacity and migration. Bioinformatic predictive analysis revealed that E3 ubiquitin ligase FBXW7 interacts directly with ZMYND8 and degrades ZMYND8 in a polyubiquitination manner. Low FBXW7 was a hazard factor for promoting and depending on accumulated ZMYND8 proteins to promote Bca progression. Gene set enrichment analysis (GSEA) further indicated that ZMYND8 was notably associated with stemness process, which was well functionally validated. Lastly, ZMYND8 deficiency was observed to inhibit tumor growth of Bca in vivo, revealing a promising translational significance in Bca treatment. In conclusion, our study for the first time provided evidence for a novel mechanism of FBXW7/ZMYND8 axis in Bca, providing therapeutic vulnerability for individualized cancer treatment.

ZMYND8 是一种表观遗传调节因子，被确定为各种肿瘤中的常见癌基因。然而，关于 ZMYND8 与膀胱癌之间关联的报道很少。此外，导致异常 ZMYND8 表达的异常机制仍不清楚。在目前的研究中，我们首先发现 Bca 样本中 ZMYND8 蛋白水平与正常组织相比显着升高，但 mRNA 水平没有。然后我们利用细胞计数试剂盒-8 (CCK-8) 测定、克隆形成测定和 transwell 分析证实 ZMYND8 可以显着促进体外肿瘤进展，包括增长能力和迁移。生物信息学预测分析表明，E3 泛素连接酶 FBXW7 直接与 ZMYND8 相互作用并以多泛素化方式降解 ZMYND8。低 FBXW7 是促进和依赖积累的 ZMYND8 蛋白促进 Bca 进展的危险因素。基因集富集分析 (GSEA) 进一步表明 ZMYND8 与干性过程显着相关，这在功能上得到了很好的验证。最后，观察到 ZMYND8 缺陷在体内抑制 Bca 的肿瘤生长，揭示了在 Bca 治疗中的有希望的转化意义。总之，我们的研究首次为 Bca 中 FBXW7/ZMYND8 轴的新机制提供了证据，为个体化癌症治疗提供了治疗脆弱性。