Protein Phosphatase Enzymes (PPE) and protein kinases simultaneously control phosphorylation mechanisms that tightly regulate intracellular signalling pathways and stimulate cellular responses. In human malignancies, PPE and protein kinases are frequently mutated resulting in uncontrolled kinase activity and PPE suppression, leading to cell proliferation, migration and resistance to anti-cancer therapies. Cancer associated DNA hypermethylation at PPE promoters gives rise to transcriptional silencing (epimutations) and is a hallmark of cancer. Despite recent advances in sequencing technologies, data availability and computational capabilities, only a fraction of PPE have been reported as transcriptionally inactive as a consequence of epimutations. In this study, we examined promoter-associated DNA methylation profiles in Protein Phosphatase Enzymes and their Interacting Proteins (PPEIP) in a cohort of 705 cancer patients in five tissues (Large intestine, Oesophagus, Lung, Pancreas and Stomach) in three cell models (primary tumours, cancer cell lines and 3D embedded cancer cell cultures). As a subset of PPEIP are known tumour suppressor genes, we analysed the impact of PPEIP promoter hypermethylation marks on gene expression, cellular networks and in a clinical setting. Here, we report epimutations in PPEIP are a frequent occurrence in the cancer genome and manifest independent of transcriptional activity. We observed that different tumours have varying susceptibility to epimutations and identify specific cellular signalling networks that are primarily affected by epimutations. Additionally, RNA-seq analysis showed the negative impact of epimutations on most (not all) Protein Tyrosine Phosphatase transcription. Finally, we detected novel clinical biomarkers that inform on patient mortality and anti-cancer treatment sensitivity. We propose that DNA hypermethylation marks at PPEIP frequently contribute to the pathogenesis of malignancies and within the precision medicine space, hold promise as biomarkers to inform on clinical features such as patient survival and therapeutic response.

中文翻译：

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蛋白磷酸酶表观遗传沉默对多种癌症组织的细胞和临床影响

蛋白磷酸酶 (PPE) 和蛋白激酶同时控制磷酸化机制，严格调节细胞内信号传导途径并刺激细胞反应。在人类恶性肿瘤中，PPE 和蛋白激酶经常发生突变，导致激酶活性失控和 PPE 抑制，导致细胞增殖、迁移和抗癌治疗耐药。癌症相关的 PPE 启动子 DNA 高甲基化会导致转录沉默（表突变），这是癌症的一个标志。尽管测序技术、数据可用性和计算能力最近取得了进展，但据报道，只有一小部分 PPE 由于表观突变而处于转录失活状态。在这项研究中，我们在三种细胞模型中检查了 705 名癌症患者的五种组织（大肠、食道、肺、胰腺和胃）中蛋白磷酸酶及其相互作用蛋白 (PPEIP) 的启动子相关 DNA 甲基化谱（原发性肿瘤、癌细胞系和 3D 嵌入式癌细胞培养物）。由于 PPEIP 的一个子集是已知的肿瘤抑制基因，我们分析了 PPEIP 启动子高甲基化标记对基因表达、细胞网络和临床环境的影响。在这里，我们报告 PPEIP 表观突变在癌症基因组中经常发生，并且表现出与转录活性无关。我们观察到不同的肿瘤对表观突变的敏感性不同，并确定了主要受表观突变影响的特定细胞信号网络。此外，RNA-seq 分析显示表观突变对大多数（不是全部）蛋白质酪氨酸磷酸酶转录产生负面影响。最后，我们检测到了新的临床生物标志物，可以告知患者死亡率和抗癌治疗敏感性。我们认为，PPEIP 中的 DNA 高甲基化标记经常导致恶性肿瘤的发病机制，并且在精准医学领域内，有望作为生物标志物来了解患者生存和治疗反应等临床特征。