Metagenomic characterization of lysine acetyltransferases in human cancer and their association with clinicopathologic features

Abstract

The dynamic and reversible acetylation of protein, catalyzed by lysine acetyltransferases (KATs, also known as HATs) and deacetylases, plays critical roles in a wide range of biological processes including transcriptional regulation, DNA damage repair, signal transduction, stem cell self-renewal, cellular metabolism, and biological rhythm. Lysine acetyltransferases are a highly diverse group of enzymes. Under the action of KATs, the acetyl group from acetyl coenzyme A is co-or posttranslationally attached to either the α-amino group of the N-terminus or the ε-amino group of lysine residues of proteins including both histone and nonhistone Abstract Lysine acetyltransferases (KATs) are a highly diverse group of epigenetic enzymes that play important roles in various cellular processes including transcription, signal transduction, and cellular metabolism. However, our knowledge of the genomic and transcriptomic alterations of KAT genes and their clinical significance in human cancer remains incomplete. We undertook a metagenomic analysis of 37 KATs in more than 10 000 cancer samples across 33 tumor types, focusing on breast cancer. We identified associations among recurrent genetic alteration, gene expression, clinicopathologic features, and patient survival. Loss-of-function analysis was carried out to examine which KAT has important roles in growth and viability of breast cancer cells. We identified that a subset of KAT genes, including NAA10, KAT6A, and CREBBP, have high frequencies of genomic amplification or mutation in a spectrum of human cancers. Importantly, we found that 3 KATs, NAA10, ACAT2, and BRD4, were highly expressed in the aggressive basal-like subtype, and their expression was significantly associated with disease-free survival. Furthermore, we showed that depletion of NAA10 inhibits basal-like breast cancer growth in vitro. Our findings provide a strong foundation for further mechanistic research and for developing therapies that target NAA10 or other KATs in human cancer. K E Y W O R D Sbreast cancer, copy number alteration, gene amplification, lysine acetyltransferase, NAA10

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

“…A second observation was that some NATs were deregulated in multiple tumour types (e.g., NAA10, NAA20, and NAA40), while others in few or none (e.g., NAA30, NAA60, NAA35). Consistent with the findings here, some of the NAT-tumour associations uncovered by the cancer vs. normal RNA expression comparison have been reported previously, such as NAA10 in lung, colorectal, liver, and breast cancer [ 18 , 19 ], NAA20 in liver [ 16 ]. We have also shown potential mechanistic links between altered DNA methylation and the deregulation of NATs in some tumours.…”

“…Compared to a collection of well-established cancer genes on which we performed the same analyses, genomic alterations of NATs are considerably lower (TP53—36%; PTEN—12%; KRAS—9%; MYC—9%; RB1—7%). We also compared NATs to 34 KATs, as defined in a recent report [ 19 ], which showed that the former are, on average, affected at a lower frequency ( Figure S1 ), and several KATs were altered in 4–6% of samples (e.g., KAT6, EP300, TAF1). On average, therefore, NAT genes are characterised by a low prevalence of mutational activity across all tumour types.…”

“…Over the past decade, the rapid technological improvements in high-throughput molecular and other multi-omic technologies, coupled with the considerable investment into collaborative consortiums such as The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) have generated a treasure trove of readily available genomic, transcriptomic, genetic dependency, and other datasets. The systematic integration of such datasets can offer important biological and medical information, for example in a recent study of 37 lysine acetyltransferases (KATs) [ 19 ]. The goal of this study was to perform a comprehensive investigation of human NATs in cancer, through a multi-omic integration of cancer datasets.…”

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

“…3 ) [ 173 ]. AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC), thereby increasing the level of acetyl-coA in tumor cells [ 174 ]. And since acetyl-CoA is the substrate for all KATs, lysine acetyltransferase activity is increased [ 175 ].…”

Detecting global influence of transcription factor interactions on gene expression in lymphoblastoid cells using neural network models

“…Another intriguing, albeit unvalidated interaction, that we discovered was EP300-TAF1(Log2NID score = 2.39). Both of these TFs are well known lysine acetyltransferases and are responsible for activating and regulating transcription of several TGs and were also found to have the highest frequency of oncogenic mutations among all the other lysine acetyltransferases [40]. The Log2NID scores for all pairwise TRMs are shown in the form of a heat-map in the Figure 2C (all scores are available in Supplementary table S3B).…”