A novel FoxM1-PSMB4 axis contributes to proliferation and progression of cervical cancer
A novel FoxM1-PSMB4 axis contributes to proliferation and progression of cervical cancer
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一种新的 FoxM1-PSMB4 轴有助于宫颈癌的增殖和进展。
DOI：
10.1016/j.bbrc.2019.10.183
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Hua Wei
中科院分区：
文献类型：
--
作者：
Zhou Dong-mei;Liu Jun;Liu Fang;Luo Guang-wei;Li Hai-tong;Zhang Rui;Chen Bi-liang;Hua Wei
蛋白酶体系统的异常高活性与多种肿瘤的发生发展密切相关。PSMB4是蛋白酶体组装的非催化亚单位。尽管来自基因筛查的报道已经证明它在几种类型的实体肿瘤中是细胞生长的驱动基因，但它在恶性肿瘤中的表达模式和调控机制仍然不清楚。在这里，我们发现PSMB4在宫颈癌组织中过表达。PSMB4基因敲除可显著抑制宫颈癌细胞的增殖。机制研究表明，FOXM1是细胞分裂的主要调节者，直接与PSMB4的启动子区域结合，并在mRNA水平上调节PSMB4的表达。此外，TCGA的数据分析显示，FxoM1和PSMB4在宫颈癌中的表达呈正相关。此外，功能和挽救实验的丧失证实了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在宫颈癌组织中表达异常的现象，并验证了其对癌细胞增殖的驱动作用。更重要的是，它强调了FOXM1-PSMB4轴可能成为治疗宫颈癌的潜在靶点。
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.