KCTD12 promotes tumorigenesis by facilitating CDC25B/CDK1/Aurora A-dependent G2/M transition.
KCTD12 promotes tumorigenesis by facilitating CDC25B/CDK1/Aurora A-dependent G2/M transition.
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KCTD12 通过促进 CDC25B/CDK1/Aurora A 依赖性 G2/M 转变来促进肿瘤发生
作者：
Zhong Y;Yang J;Xu WW;Wang Y;Zheng CC;Li B;He QY
细胞周期失调导致不受控制的细胞增殖和肿瘤发生。了解细胞周期进程的分子机制可以为识别参与癌症发展的关键蛋白提供线索。在这项研究中，我们进行了蛋白质组学分析，以确定新的细胞周期调节因子。我们发现含12的钾通道四聚域（KCTD12）在M期与S期相比显著上调。我们还发现，KCTD12过表达不仅促进了G2/M的转化，诱导了癌细胞的增殖，还促进了小鼠皮下肿瘤的生长和Ki-67增殖指数。细胞周期蛋白依赖性激酶1 （cyclin-dependent kinase 1, CDK1）通过免疫沉淀和质谱分析被确定为KCTD12的相互作用伙伴，这表明KCTD12激活了CDK1和极光激酶A (Aurora A)，而KCTD12对CDK1磷酸化和细胞增殖的影响被细胞分裂周期25B （CDC25B）沉默所消除。此外，Aurora A磷酸化了KCTD12的243号丝氨酸，从而启动了KCTD12发挥其促癌作用所必需的正反馈回路。此外，我们使用肿瘤组织微阵列和基因表达Omnibus （GEO）数据集分析了各种基因的表达水平以及这些基因表达与生存之间的关系。数据显示，KCTD12在宫颈癌和肺癌中的表达显著上调。更重要的是，KCTD12高表达与较大的肿瘤大小、较高的病理分期和较差的患者生存率相关。总之，我们的研究表明，KCTD12结合CDC25B，激活CDK1和Aurora A，促进G2/M转变并促进肿瘤发生，Aurora A磷酸化KCTD12在丝氨酸243处触发正反馈回路，从而增强KCTD12的作用。因此，KCTD12-CDC25B-CDK1-Aurora A轴对癌症诊断和预后具有重要意义。
Cell cycle dysregulation leads to uncontrolled cell proliferation and tumorigenesis. Understanding the molecular mechanisms underlying cell cycle progression can provide clues leading to the identification of key proteins involved in cancer development. In this study, we performed proteomics analysis to identify novel regulators of the cell cycle. We found that potassium channel tetramerization domain containing 12 (KCTD12) was significantly upregulated in M phase compared with S phase. We also found that KCTD12 overexpression not only facilitated the G2/M transition and induced cancer cell proliferation, but also promoted the growth of subcutaneous tumors and Ki-67 proliferation index in mice. Regarding the mechanism underlying these phenomena, cyclin-dependent kinase 1 (CDK1) was identified as an interacting partner of KCTD12 by immunoprecipitation and mass spectrometry analysis, which showed that KCTD12 activated CDK1 and Aurora kinase A (Aurora A) and that the effects of KCTD12 on CDK1 phosphorylation and cell proliferation were abrogated by cell division cycle 25B (CDC25B) silencing. In addition, Aurora A phosphorylated KCTD12 at serine 243, thereby initiating a positive feedback loop necessary for KCTD12 to exert its cancer-promoting effects. Furthermore, we analyzed the expression levels of various genes and the correlations between the expression of these genes and survival using tumor tissue microarray and Gene Expression Omnibus (GEO) data sets. The data showed that KCTD12 expression was significantly upregulated in cervical and lung cancers. More importantly, high KCTD12 expression was associated with larger tumor sizes, higher pathological stages and poor patient survival. Collectively, our study demonstrate that KCTD12 binds to CDC25B and activates CDK1 and Aurora A to facilitate the G2/M transition and promote tumorigenesis and that Aurora A phosphorylates KCTD12 at serine 243 to trigger a positive feedback loop, thereby potentiating the effects of KCTD12. Thus, the KCTD12-CDC25B-CDK1-Aurora A axis has important implications for cancer diagnoses and prognoses.
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