Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
Departments of Oncology, Biochemistry and Molecular Biology, Cumming School of Medicine, Calgary, AB T2N 4N1, Canada.
Int J Mol Sci. 2022 Nov 1;23(21):13326. doi: 10.3390/ijms232113326.
Prostate cancer (PCa) is one of the most commonly diagnosed types of malignancy and is the second leading cause of cancer-related death in men in developed countries. Cyclin dependent kinase 2 associate protein 1(CDK2AP1) is an epigenetic and cell cycle regulator gene which has been downregulated in several malignancies, but its involvement in PCa has not yet been investigated in a clinical setting. We assessed the prognostic value of CDK2AP1 expression in a cohort of men diagnosed with PCa (n = 275) treated non-surgically by transurethral resection of the prostate (TURP) and studied the relationship between CDK2AP1 expression to various PCa molecular subtypes (ERG, PTEN, p53 and AR) and evaluated the association with clinical outcome. Further, we used bioinformatic tools to analyze the available TCGA PRAD transcriptomic data to explore the underlying mechanism. Our data confirmed increased expression of CDK2AP1 with higher Gleason Grade Group (GG) and metastatic PCa (p <0.0001). High CDK2AP1 expression was associated with worse overall survival (OS) (HR: 1.62, CI: 1.19−2.21, p = 0.002) and cause-specific survival (CSS) (HR: 2.012, CI 1.29−3.13, p = 0.002) using univariate analysis. When compared to each sub-molecular type. High CDK2AP1/PTEN-loss, abnormal AR or p53 expression showed even worse association to poorer OS and CCS and remained significant when adjusted for GG. Our data indicates that CDK2AP1 directly binds to p53 using the Co-Immunoprecipitation (Co-IP) technique, which was validated using molecular docking tools. This suggests that these two proteins have a significant association through several binding features and correlates with our observed clinical data. In conclusion, our results indicated that the CDK2AP1 overexpression is associate with worse OS and CSS when combined with certain PCa molecular subtypes; interaction between p53 stands out as the most prominent candidate which directly interacts with CDK2AP1.
前列腺癌 (PCa) 是最常见的恶性肿瘤之一，也是发达国家男性癌症相关死亡的第二大主要原因。细胞周期蛋白依赖性激酶 2 相关蛋白 1 (CDK2AP1) 是一种表观遗传和细胞周期调节基因，已在多种恶性肿瘤中下调，但尚未在临床环境中研究其在 PCa 中的作用。我们评估了 CDK2AP1 表达在一组接受经尿道前列腺切除术 (TURP) 非手术治疗的 PCa 患者 (n = 275)中的预后价值，并研究了 CDK2AP1 表达与各种 PCa 分子亚型 (ERG、PTEN、p53 和 AR) 之间的关系，并评估了与临床结果的关联。此外，我们使用生物信息学工具分析了可用的 TCGA PRAD 转录组数据，以探讨潜在的机制。我们的数据证实，随着 Gleason 分级组 (GG) 和转移性 PCa 的升高，CDK2AP1 的表达增加 (p <0.0001)。高 CDK2AP1 表达与总体生存 (OS) (HR: 1.62, CI: 1.19−2.21, p = 0.002) 和特定原因生存 (CSS) (HR: 2.012, CI 1.29−3.13, p = 0.002) 呈负相关。在单变量分析中。与每个亚分子类型相比。高 CDK2AP1/PTEN 缺失、异常 AR 或 p53 表达与更差的 OS 和 CSS 相关性更强，并且在调整 GG 后仍然具有统计学意义。我们的数据表明，CDK2AP1 使用免疫共沉淀 (Co-IP) 技术直接与 p53 结合，这通过分子对接工具得到了验证。这表明这两种蛋白质通过几个结合特征具有显著的关联，并与我们观察到的临床数据相关。总之，我们的结果表明，当与某些 PCa 分子亚型结合时，CDK2AP1 的过表达与更差的 OS 和 CSS 相关；p53 之间的相互作用最为突出，p53 与 CDK2AP1 直接相互作用。
