Department of Obstetrics and Gynecology, Xijing Hospital, Fourth Military Medical University, 710032, Xi'an, China.
State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032, Xi'an, China.
Biochem Biophys Res Commun. 2020 Jan 15;521(3):746-752. doi: 10.1016/j.bbrc.2019.10.183. Epub 2019 Nov 5.
The abnormally high activity of the proteasome system is closely related to the occurrence and development of various tumors. PSMB4 is a non-catalytic subunit for the proteasome assembly. Although the reports from genetic screening have demonstrated it's a driver gene for cell growth in several types of solid tumor, its expression pattern and regulatory mechanisms in malignant diseases are still elusive. Here, we found that PSMB4 is overexpressed in cervical cancer tissues. And knockdown of PSMB4 significantly inhibited cervical cancer cell proliferation. The mechanistic study revealed that FoxM1, a master regulator of cell division, binds directly to the promoter region of PSMB4 and regulates the PSMB4 expression in the mRNA level. In addition, the data analysis from TCGA showed a positive correlation between FxoM1 and PSMB4 in cervical cancer. Furthermore, the loss of functional and rescue experiments confirmed that PSMB4 is required for FoxM1-driven cervical cancer cell proliferation. Collectively, our study explains the phenomenon of dysregulated expression of PSMB4 in cervical cancer tissues and verifies its driver effect on cancer cell proliferation. More importantly, it highlights a FoxM1-PSMB4 axis could be a potential target for the treatment of cervical cancer.
蛋白酶体系统的异常高活性与各种肿瘤的发生和发展密切相关。PSMB4 是蛋白酶体组装的非催化亚基。尽管遗传筛选的报告表明它是几种实体瘤中细胞生长的驱动基因，但它在恶性疾病中的表达模式和调控机制仍不清楚。在这里，我们发现 PSMB4 在宫颈癌组织中过表达。敲低 PSMB4 显著抑制了宫颈癌细胞的增殖。机制研究表明，细胞分裂的主调控因子 FoxM1 直接结合 PSMB4 的启动子区域，并在 mRNA 水平上调节 PSMB4 的表达。此外，TCGA 的数据分析显示宫颈癌中 FoxM1 和 PSMB4 之间存在正相关。此外，功能丧失和挽救实验证实 PSMB4 是 FoxM1 驱动的宫颈癌细胞增殖所必需的。总之，我们的研究解释了 PSMB4 在宫颈癌组织中失调表达的现象，并验证了它对癌细胞增殖的驱动作用。更重要的是，它强调了 FoxM1-PSMB4 轴可能是治疗宫颈癌的潜在靶点。
