文章：

切割与聚腺苷酸化机制是人类癌症中一个可靶向的新型脆弱点

Cleavage and polyadenylation machinery as a novel targetable vulnerability for human cancer 

原文发布日期：2024-04-17 

英文摘要：

The role of alternative polyadenylation of mRNA in sustaining aggressive features of tumors is quite well established, as it is responsible for the 3’UTR shortening of oncogenes and subsequent relief from miRNA-mediated repression observed in cancer cells. However, the information regarding the vulnerability of cancer cells to the inhibition of cleavage and polyadenylation (CPA) machinery is very scattered. Only few recent reports show the antitumor activity of pharmacological inhibitors of CPSF3, one among CPA factors. More in general, the fact that deregulated CPA can be seen as a new hallmark of cancer and as a potential reservoir of novel therapeutic targets has never been formalized. Here, to extend our view on the potential of CPA inhibition (CPAi) approaches as anticancer therapies, we systematically tested the fitness of about one thousand cell lines of different cancer types upon depletion of all known CPA factors by interrogating genome-scale CRISPR and RNAi dependency maps of the DepMap project. Our analysis confirmed core and accessory CPA factors as novel vulnerabilities for human cancer, thus highlighting the potential of CPAi as anticancer therapy. Among all, CPSF1 appeared as a promising actionable candidate for drug development, as it showed low dependency scores pancancer and particularly in highly proliferating cells. In a personalized medicine perspective, the observed differential vulnerability of cancer cell lines to selected CPA factors may be used to build up signatures to predict response of individual human tumors to CPAi approaches. 

摘要翻译：

mRNA可变多聚腺苷酸化在维持肿瘤侵袭性特征中的作用已较为明确，它通过缩短癌基因的3'非翻译区并解除miRNA介导的抑制效应（该现象常见于癌细胞）。然而关于癌细胞对剪切与多聚腺苷酸化（CPA）机制抑制的脆弱性信息仍十分零散。近期仅有少数报道显示CPSF3（CPA因子之一）的药理抑制剂具有抗肿瘤活性。更广泛而言，CPA失调可视为癌症新特征和潜在治疗靶点库这一观点尚未得到系统阐述。本研究为拓展CPA抑制（CPAi）方法作为抗癌疗法的潜力，通过DepMap项目的基因组规模CRISPR和RNAi依赖性图谱，系统检测了约一千种不同癌症类型细胞系在所有已知CPA因子耗竭后的适应性。我们的分析证实核心与辅助CPA因子是人类癌症的新脆弱点，从而凸显了CPAi作为抗癌疗法的潜力。其中CPSF1因在全癌种（尤其在高速增殖细胞中）表现出低依赖性评分，成为药物开发中有前景的候选靶点。从精准医学视角来看，观测到的癌细胞系对特定CPA因子的差异脆弱性可用于构建特征标签，以预测个体人类肿瘤对CPAi方法的反应。

原文链接：

Cleavage and polyadenylation machinery as a novel targetable vulnerability for human cancer