Department of Urology, Fudan University Shanghai Cancer Center, 200032, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China.
Oncogene. 2024 Mar;43(10):744-757. doi: 10.1038/s41388-024-02945-1. Epub 2024 Jan 19.
Androgen receptors (ARs) play key roles in prostate cancer (PCa) progression and castration-resistant prostate cancer (CRPC) resistance to drug therapy. SET and MYND domain containing protein 2 (SMYD2), a lysine methyltransferase, has been reported to promote tumors by transcriptionally methylating important oncogenes or tumor repressor genes. However, the role of SMYD2 in CRPC drug resistance remains unclear. In this study, we found that SMYD2 expression was significantly upregulated in PCa tissues and cell lines. High SMYD2 expression indicated poor CRPC-free survival and overall survival in patients. SMYD2 knockdown dramatically inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) potential of 22Rv1 and C4-2 cells. Conversely, ectopic overexpression of SMYD2 promoted these effects in 22Rv1 and C4-2 cells. Mechanistically, SMYD2 methylated and phosphorylated ARs to affect AR ubiquitination and proteasome degradation, which further alters the AR transcriptome in CRPC cells. Importantly, the SMYD2 inhibitor AZ505 had a synergistic therapeutic effect with enzalutamide in CRPC cells and mouse models; however, it could also re-sensitize resistant CRPC cells to enzalutamide. Our findings demonstrated that SMYD2 enhances the methylation and phosphorylation of ARs and affects AR ubiquitination and proteasome degradation to modulate CRPC cell resistance to enzalutamide, indicating that SMYD2 serves as a crucial oncogene in PCa and is an ideal therapeutic target for CRPC.
雄激素受体（ARs）在前列腺癌（PCa）进展和去势抵抗性前列腺癌（CRPC）对药物治疗的耐药性中发挥关键作用。SET 和 MYND 结构域包含蛋白 2（SMYD2）是一种赖氨酸甲基转移酶，据报道通过转录甲基化重要的癌基因或肿瘤抑制基因来促进肿瘤。然而，SMYD2 在 CRPC 耐药性中的作用尚不清楚。在这项研究中，我们发现 SMYD2 在 PCa 组织和细胞系中表达明显上调。高 SMYD2 表达表明患者的 CRPC 无复发生存和总生存不良。SMYD2 敲低显著抑制 22Rv1 和 C4-2 细胞的增殖、迁移、侵袭和上皮-间充质转化（EMT）潜能。相反，外源性过表达 SMYD2 促进了 22Rv1 和 C4-2 细胞的这些效应。在机制上，SMYD2 甲基化和磷酸化 ARs 以影响 AR 的泛素化和蛋白酶体降解，从而进一步改变 CRPC 细胞中的 AR 转录组。重要的是，SMYD2 抑制剂 AZ505 与恩扎鲁胺在 CRPC 细胞和小鼠模型中具有协同治疗作用；然而，它也可以使耐药性 CRPC 细胞重新对恩扎鲁胺敏感。我们的研究结果表明，SMYD2 增强了 AR 的甲基化和磷酸化，并影响了 AR 的泛素化和蛋白酶体降解，从而调节 CRPC 细胞对恩扎鲁胺的耐药性，表明 SMYD2 是 PCa 中的关键癌基因，是 CRPC 的理想治疗靶点。
