PRR11 and SKA2 gene pair is overexpressed and regulated by p53 in breast cancer
PRR11 and SKA2 gene pair is overexpressed and regulated by p53 in breast cancer
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PRR11 和 SKA2 基因对在乳腺癌中过度表达并受 p53 调节
DOI：
10.5483/bmbrep.2019.52.2.207
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发表时间：
2019-02-28
期刊：
影响因子：
3.8
通讯作者：
Bu, Youquan
中科院分区：
文献类型：
--
作者：
Wang, Yitao;Zhang, Chunxue;Bu, Youquan
我们前期的研究发现，两个新的癌症相关基因PRR11和SKA2在肺癌中构成了一个由p53和NF-Y调控的经典基因对。然而，它们在乳腺癌中的作用和调控机制尚不清楚。在本研究中，我们发现PRR11和SKA2的表达水平上调，在乳腺癌中具有阴性预后价值。功能缺失实验表明，rnai介导的PRR11和/或SKA2的下调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的敲低会导致CDK6、TPM3、USP12等下游基因的失调。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的表达至关重要并与之相关，而对SKA2则无关。与此一致的是，阿霉素诱导的内源性p53激活也导致PRR11和SKA2基因对表达的显著抑制。值得注意的是，与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表达水平较低的乳腺癌患者以及野生型p53表现出更好的无病生存率。总之，我们的研究表明，PRR11和SKA2转录单位可能是致癌因子，并可能作为乳腺癌新的诊断和治疗靶点。
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.