N-Terminal Acetyltransferases Are Cancer-Essential Genes Prevalently Upregulated in Tumours

SIMPLE SUMMARY: 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. ABSTRACT: 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.