Li Min, Cui Chuanyou, Li Jiawei, Zhou Jianfeng, Chen Shen, Yan Jinqiang, Zhang Di, Zhang Yifei, Xie Panpan, Yao Yumin, Ni Feixue, An Meng, Zhang Wei, Fu Bo
Department of Precision Biomedical Key Laboratory, Liaocheng People's Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University; Shandong Provincial Key Medical and Health Laboratory of Precision Medicine for Aging Intervention and Active Health, Liaocheng 252000, China.
Department of General Surgery, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China; Department of Breast and Thyroid Surgery, Liaocheng People's Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China.
Cell Signal. 2025 Nov;135:112022. doi: 10.1016/j.cellsig.2025.112022. Epub 2025 Jul 28.
During the metastatic progression of cancer, tumor cells undergo widespread genetic and epigenetic alterations. The regulatory mechanism of 5-methylcytosine (mC) methylation of PSD4 in breast cancer brain metastasis (BCBM) remains unclear. In this study, we found that PSD4 expression is markedly elevated in both BCBM tissues and cell lines. Functional assays in vitro revealed that overexpression of PSD4 significantly promoted cell proliferation, invasion, migration, and epithelial-to-mesenchymal transition (EMT). Complementary in vivo experiments confirmed the tumor-promoting and metastasis-enhancing roles of PSD4 in brain metastases. At the mechanistic level, PSD4 mC methylation was regulated by NSUN2 via its catalytic domains (C271A/C321A), which enhanced PSD4 mRNA stability and facilitated its nuclear export, increasing its expression. Furthermore, YBX1 was identified as a critical mC-binding protein regulating PSD4 methylation. Functional analysis also showed that PSD4 contributes to vasculogenic mimicry (VM) by promoting ferroptosis resistance, decreasing vascular permeability, and enhancing tumor growth and metastasis to the brain. These findings establish PSD4 as a key player in BCBM and suggest its potential as a diagnostic marker and therapeutic target.
在癌症的转移进程中，肿瘤细胞会发生广泛的基因和表观遗传改变。乳腺癌脑转移（BCBM）中PSD4的5-甲基胞嘧啶（mC）甲基化调控机制仍不清楚。在本研究中，我们发现PSD4在BCBM组织和细胞系中表达均显著升高。体外功能实验表明，PSD4的过表达显著促进细胞增殖、侵袭、迁移及上皮-间质转化（EMT）。体内补充实验证实了PSD4在脑转移中的促肿瘤和增强转移作用。在机制层面，PSD4的mC甲基化由NSUN2通过其催化结构域（C271A/C321A）调控，这增强了PSD4 mRNA的稳定性并促进其核输出，增加其表达。此外，YBX1被鉴定为调节PSD4甲基化的关键mC结合蛋白。功能分析还表明，PSD4通过促进铁死亡抗性、降低血管通透性以及增强肿瘤生长和向脑转移，对血管生成拟态（VM）有贡献。这些发现确立了PSD4作为BCBM中的关键因子，并表明其作为诊断标志物和治疗靶点的潜力。
