Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China.
Laboratory of Birth Defects and Related Diseases of Women and Children, West China Second University Hospital, Sichuan University, Chengdu 610000, China.
BMB Rep. 2019 Feb;52(2):157-162. doi: 10.5483/BMBRep.2019.52.2.207.
Our previous study found that two novel cancer-related genes, PRR11 and SKA2, constituted a classic gene pair that was regulated by p53 and NF-Y in lung cancer. However, their role and regulatory mechanism in breast cancer remain elusive. In this study, we found that the expression levels of PRR11 and SKA2 were upregulated and have a negative prognotic value in breast cancer. Loss-of-function experiments showed that RNAi-mediated knockdown of PRR11 and/or SKA2 inhibited proliferation, migration, and invasion of breast cancer cells. Mechanistic experiments revealed that knockdown of PRR11 and/or SKA2 caused dysregulation of several downstream genes, including CDK6, TPM3, and USP12, etc. Luciferase reporter assays demonstrated that wild type p53 significantly repressed the PRR11-SKA2 bidirectional promoter activity, but not NF-Y. Interestingly, NF-Y was only essential for and correlated with the expression of PRR11, but not SKA2. Consistently, adriamycin-induced (ADR) activation of endogenous p53 also caused significant repression of the PRR11 and SKA2 gene pair expression. Notably, breast cancer patients with lower expression levels of either PRR11 or SKA2, along with wild type p53, exhibited better disease-free survival compared to others with p53 mutations and/or higher expression levels of either PRR11 or SKA2. Collectively, our study indicates that the PRR11 and SKA2 transcription unit might be an oncogenic contributor and might serve as a novel diagnostic and therapeutic target in breast cancer. [BMB Reports 2019; 52(2): 157-162].
我们之前的研究发现，两个新的癌症相关基因 PRR11 和 SKA2 构成了一个经典的基因对，受肺癌中 p53 和 NF-Y 的调控。然而，它们在乳腺癌中的作用和调节机制仍不清楚。在这项研究中，我们发现 PRR11 和 SKA2 的表达水平上调，并且对乳腺癌具有负预后价值。功能丧失实验表明，RNAi 介导的 PRR11 和/或 SKA2 敲低抑制了乳腺癌细胞的增殖、迁移和侵袭。机制实验表明，PRR11 和/或 SKA2 的敲低导致包括 CDK6、TPM3 和 USP12 等几个下游基因的失调。荧光素酶报告基因实验表明，野生型 p53 显著抑制 PRR11-SKA2 双向启动子活性，但不抑制 NF-Y。有趣的是，NF-Y 仅对 PRR11 的表达是必需的和相关的，而对 SKA2 的表达则不是。一致地，阿霉素诱导（ADR）激活内源性 p53 也导致 PRR11 和 SKA2 基因对表达的显著抑制。值得注意的是，与其他具有 p53 突变和/或 PRR11 或 SKA2 表达水平较高的乳腺癌患者相比，PRR11 或 SKA2 表达水平较低且具有野生型 p53 的乳腺癌患者具有更好的无病生存。总之，我们的研究表明，PRR11 和 SKA2 转录单元可能是致癌基因的贡献者，并可能成为乳腺癌的一种新的诊断和治疗靶点。[BMB 报告 2019；52(2):157-162]。
