Dissecting the oncogenic properties of essential RNA-modifying enzymes: a focus on NAT10

Abstract

Chemical modifications of ribonucleotides significantly alter the physicochemical properties and functions of RNA. Initially perceived as static and essential marks in ribosomal RNA (rRNA) and transfer RNA (tRNA), recent discoveries unveiled a dynamic landscape of RNA modifications in messenger RNA (mRNA) and other regulatory RNAs. These findings spurred extensive efforts to map the distribution and function of RNA modifications, aiming to elucidate their distribution and functional significance in normal cellular homeostasis and pathological states. Significant dysregulation of RNA modifications is extensively documented in cancers, accentuating the potential of RNA-modifying enzymes as therapeutic targets. However, the essential role of several RNA-modifying enzymes in normal physiological functions raises concerns about potential side effects. A notable example is N-acetyltransferase 10 (NAT10), which is responsible for acetylating cytidines in RNA. While emerging evidence positions NAT10 as an oncogenic factor and a potential target in various cancer types, its essential role in normal cellular processes complicates the development of targeted therapies. This review aims to comprehensively analyze the essential and oncogenic properties of NAT10. We discuss its crucial role in normal cell biology and aging alongside its contribution to cancer development and progression. We advocate for agnostic approaches to disentangling the intertwined essential and oncogenic functions of RNA-modifying enzymes. Such approaches are crucial for understanding the full spectrum of RNA-modifying enzymes and imperative for designing effective and safe therapeutic strategies.

Fig. 1.. NAT10 is an essential gene.

A Schematic representation of the essential and oncogenic properties of NAT10. B-C The list of RNA-modifying enzymes was obtained from MODOMICS. The CRISPR score and perturbation effects were downloaded from DepMap and graphed as a heat map for all RNA-modifying enzymes (B) or as box plots for NAT10 in different cell lineages (C).

Fig. 2.. NAT10 is a cancer-promoting factor.

A The list of NAT10 and TP53 mutations in cancer was obtained from cBioportal. B The box plots represent the NAT10 protein levels in normal tissues and three different tumor types obtained from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the International Cancer Proteogenome Consortium (ICPC) datasets. The Images were downloaded from The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN) database. C Data represent the fold change in NAT10 mRNA levels between normal and tumor tissues for different cancer types. mRNA levels in normal and tumor tissues, along with the p-values of the normal vs. tumor comparisons, were obtained from The Cancer Genome Atlas Program (TCGA) through the UALCAN database. In red are tumors in which NAT10 is significantly higher than normal tissues. D Kaplan-Meier survival curves comparing NAT10 expression using the TCGA data. Survival curves were downloaded from the UALCAN database. p = long-rank test. E Schematic representation of NAT10’s localization in normal and cancerous cells.

Fig. 3.. Structural and molecular functions of NAT10.

A. Linear representation of NAT10’s domains. B. The 3D structure of NAT10 was downloaded from AlphaFold (ID: AF-Q9H0A0-F1 | Model). Domains were color-coded using PyMOL. C. Schematic representation of all molecular functions of NAT10. The chemical structures were drawn using ChemDraw, and the 3D structure was downloaded from the protein data bank (PDB: 6rxu). NAT10 homodimers were color-coded using PyMOL. D. snoRNAs guide NAT10-dependent rRNA acetylation, whereas tRNA acetylation is guided by THUMPD1. The mechanisms of mRNA acetylation and protein by NAT10 are still unknown.

Fig. 4.

Role of NAT10 in different cellular processes.