Chen Chun-Chi, Chu Pei-Yi, Lin Hung-Yu
Section of Urology, Departments of Surgery, Changhua Christian Hospital, Changhua 500, Taiwan.
Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan.
Life (Basel). 2022 Oct 30;12(11):1742. doi: 10.3390/life12111742.
Prostate adenocarcinoma (PRAD) is the most common histological subtype of prostate cancer. Post-treatment biochemical recurrence is a challenging issue. ATAD1 (ATPase Family AAA Domain Containing 1) plays a vital role in mitochondrial proteostasis and apoptosis activity, while its clinical value in PRAD and its impact on the tumor microenvironment (TME) remain unanswered. In this study, we aimed to investigate the clinical value and possible mechanisms of ATAD1 in PRAD via multi-omics analysis. Using cBioPortal, we confirmed that ATAD1 alteration was associated with gene expression and unfavorable DFS. Deep deletion predominantly occurred in PRAD. By integrating DriverDBv3 and GEPIA2, we noted ATAD1 downregulation in PRAD tissues compared to normal tissues, associated with unfavorable DFS in PRAD patients. DNA repair genes ATM, PARP1and BRCA2 had positive associations with ATAD1 expression. We found that the generalization value of ATAD1 could be applied to other cancers such as KIRC and UCEC. In addition, LinkedOmics identified that the functional involvement of ATAD1 participates in mitochondrial structure and cell cycle progression. Using TIMER analysis, we demonstrated that ATAD1 downregulation correlated with an immunosuppressive TME. Furthermore, we accessed a GSE55062 dataset on UALCAN and discovered the involvement of ERG-mediated transcriptional repression on ATAD1 downregulation. Cross-association screening of shATAD1 efficacy vs. altered mRNAs identified 190 perturbed mRNAs. Then, functional enrichment analysis using the Metascape omics tool recognized that shATAD1-perturbed mRNAs are primarily in charge of the activation of Wnt/β-catenin pathway and lipid metabolic processes. In conclusion, multi-omics results reveal that ATAD1 downregulation is a clinical biomarker for pathological diagnosis and prognosis for patients with PRAD. Reduced ATAD1 may be involved in the enhanced activity of mitochondria and cell cycle, as well as possibly shaping an immunosuppressive TME. ERG serves as an upstream transcriptional repressor of ATAD1. Downstream mechanisms of ATAD1 are involved in Wnt/β-catenin pathway and lipid metabolic processes.
前列腺腺癌（PRAD）是前列腺癌最常见的组织学亚型。治疗后生化复发是一个具有挑战性的问题。ATAD1（含ATP酶家族AAA结构域1）在线粒体蛋白质稳态和凋亡活性中起重要作用，但其在PRAD中的临床价值及其对肿瘤微环境（TME）的影响仍未明确。在本研究中，我们旨在通过多组学分析探讨ATAD1在PRAD中的临床价值及可能机制。使用cBioPortal，我们证实ATAD1改变与基因表达及不良无病生存期（DFS）相关。深度缺失主要发生在PRAD中。通过整合DriverDBv3和GEPIA2，我们注意到与正常组织相比，PRAD组织中ATAD1表达下调，这与PRAD患者的不良DFS相关。DNA修复基因ATM、PARP1和BRCA2与ATAD1表达呈正相关。我们发现ATAD1的普遍化价值可应用于其他癌症，如肾透明细胞癌（KIRC）和子宫内膜癌（UCEC）。此外，LinkedOmics鉴定出ATAD1的功能参与线粒体结构和细胞周期进程。使用TIMER分析，我们证明ATAD1下调与免疫抑制性TME相关。此外，我们在UALCAN上获取了一个GSE55062数据集，并发现ERG介导的转录抑制与ATAD1下调有关。shATAD1疗效与mRNA改变的交叉关联筛选确定了190个受干扰的mRNA。然后，使用Metascape组学工具进行功能富集分析发现，shATAD1干扰的mRNA主要负责Wnt/β-连环蛋白途径的激活和脂质代谢过程。总之，多组学结果表明，ATAD1下调是PRAD患者病理诊断和预后的临床生物标志物。ATAD1减少可能参与线粒体和细胞周期活性增强，以及可能形成免疫抑制性TME。ERG作为ATAD1的上游转录抑制因子。ATAD1的下游机制参与Wnt/β-连环蛋白途径和脂质代谢过程。
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