N-Terminal Acetyltransferases Are Cancer-Essential Genes Prevalently Upregulated in Tumours.
N-Terminal Acetyltransferases Are Cancer-Essential Genes Prevalently Upregulated in Tumours.
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DOI：
10.3390/cancers12092631
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发表时间：
2020-09-15
期刊：
影响因子：
5.2
通讯作者：
Kirmizis A
中科院分区：
文献类型：
--
作者：
Koufaris C;Kirmizis A
癌症仍然是全球死亡的主要原因之一。最终，癌症是由控制细胞生长和行为的正常机制被破坏所驱动的。我们对这些正常细胞控制机制如何在癌症中被破坏的认识的改进可能会带来更好的诊断和新的治疗方法。在这项研究中，我们通过分析现有的大规模癌症相关数据集，研究了编码蛋白n端乙酰转移酶（NATs）的特定基因家族在各种类型肿瘤中的作用。我们报告了一些关于NATs在癌症中如何被破坏的新发现，突出了NATs可能具有生物学重要性并可能作为治疗靶点的特定肿瘤。n端乙酰化（Nt-Ac）是一种丰富的真核蛋白修饰，由催化和潜在辅助亚基组成的七种n端乙酰转移酶（NAT）复合物中的一种沉积在人体内。人们越来越认识到NATs与癌症的关系，但目前缺乏系统的跨肿瘤评估。为了解决这一限制，我们在这里对NATs进行了多组数据查询。我们发现NATs或其蛋白质底物的肿瘤基因组改变通常是罕见的事件，有一些肿瘤特异性例外。相反，癌症中NATs基因表达的改变及其与患者生存的关系构成了一种普遍的癌症现象。依赖筛选结果表明：(1)除NAA60、NAA80和NAA11、NAA16外，其余10个NAT基因均在最依赖基因的前80百分位范围内；NATs通过不同的生物过程起作用。NAA40 （NatD）作为一种具有特别有趣的癌症生物学和治疗潜力的NAT出现，特别是在肝癌中，其在多项研究中的表达增加及其与患者生存的关联支持了一种新的致癌作用。总之，这项研究产生的见解和数据将极大地帮助指导进一步研究NATs在癌症中的功能和治疗潜力。
Cancer remains one of the leading causes of mortality globally. Ultimately, cancers are driven by the disruption of normal mechanisms that control the growth and behaviour of our cells. Improvements in our knowledge of how these normal cell control mechanisms are disrupted in cancers can potentially lead to better diagnosis and new treatments. In this study, we examined the involvement of a specific gene family, encoding protein N-terminal acetyltransferases (NATs), in various types of tumours by analysing available large-scale cancer-associated datasets. We report several novel findings relating to how NATs are disrupted in cancers highlighting specific tumours where NATs can be of biological importance and may serve as therapeutic targets. N-terminal acetylation (Nt-Ac) is an abundant eukaryotic protein modification, deposited in humans by one of seven N-terminal acetyltransferase (NAT) complexes composed of a catalytic and potentially auxiliary subunits. The involvement of NATs in cancers is being increasingly recognised, but a systematic cross-tumour assessment is currently lacking. To address this limitation, we conducted here a multi-omic data interrogation for NATs. We found that tumour genomic alterations of NATs or of their protein substrates are generally rare events, with some tumour-specific exceptions. In contrast, altered gene expression of NATs in cancers and their association with patient survival constitute a widespread cancer phenomenon. Examination of dependency screens revealed that (i), besides NAA60 and NAA80 and the NatA paralogues NAA11 and NAA16, the other ten NAT genes were within the top 80th percentile of the most dependent genes (ii); NATs act through distinct biological processes. NAA40 (NatD) emerged as a NAT with particularly interesting cancer biology and therapeutic potential, especially in liver cancer where a novel oncogenic role was supported by its increased expression in multiple studies and its association with patient survival. In conclusion, this study generated insights and data that will be of great assistance in guiding further research into the function and therapeutic potential of NATs in cancer.