A Review of Research on the Mechanism of Tumor Regulation by N-Acetyltransferase 10.

N-acetyltransferase 10 (NAT10) is an important acetyltransferase that regulates telomerase activity and participates in DNA damage reactions, ribosomal RNA (rRNA) transcriptional activation, cell division, microtubule acetylation, and other important cellular processes. Abnormalities in the expression or distribution of NAT10 result in diseases such as Hutchinson-Gilford progeria syndrome (HGPS) and various tumors, with serious consequences. Remodelin, an inhibitor of NAT10, delays HGPS progression; many studies have been conducted on its role in tumor therapy. A major breakthrough in the study of NAT10 was the discovery of mRNA N4-acetylcytidine (ac4C) modification, which can increase mRNA stability and translation efficiency significantly. In addition, NAT10 modifies the mRNA of ac4C, which is associated with tumor development. Here, we present a review of pertinent studies focusing on NAT10, particularly its role in cancer, to provide researchers with a concise and informative summary of the current state of knowledge about this topic. The conclusions drawn from this review could provide a new direction for tumor treatment.

A four-year-old girl with pathogenic variant in the NAA10 gene and precocious puberty - case report and literature review.

The NAA10 gene encodes N-alpha-acetyltransferase 10 which plays an important role in cell growth, differentiation, DNA damage, metastasis, apoptosis, stress response and autophagy. Defects in the NAA10 gene correlate with the diagnosis of NAA10-related syndrome (Ogden syndrome). The most common symptoms of NAA10-related syndrome are: global developmental delay, non-verbal or limited speech, autism spectrum disorder, feeding difficulties, motor delay, muscle tone disturbances, and long QT syndrome. To-date, there are about 100 patients who have been reported with this condition. The case report presents the clinical study of a girl aged 4 years and 3 months diagnosed with Ogden syndrome. She had many characteristic features of the disorder, as well as precocious puberty. This girl represents the case of a patient with p.Arg83Cys mutation in NAA10 gene as well as precocious puberty.

Acetylcytidine modification of Amotl1 by N-acetyltransferase 10 contributes to cardiac fibrotic expansion in mice after myocardial infarction.

Cardiac fibrosis is a pathological scarring process that impairs cardiac function. N-acetyltransferase 10 (Nat10) is recently identified as the key enzyme for the N4-acetylcytidine (ac4C) modification of mRNAs. In this study, we investigated the role of Nat10 in cardiac fibrosis following myocardial infarction (MI) and the related mechanisms. MI was induced in mice by ligation of the left anterior descending coronary artery; cardiac function was assessed with echocardiography. We showed that both the mRNA and protein expression levels of Nat10 were significantly increased in the infarct zone and border zone 4 weeks post-MI, and the expression of Nat10 in cardiac fibroblasts was significantly higher compared with that in cardiomyocytes after MI. Fibroblast-specific overexpression of Nat10 promoted collagen deposition and induced cardiac systolic dysfunction post-MI in mice. Conversely, fibroblast-specific knockout of Nat10 markedly relieved cardiac function impairment and extracellular matrix remodeling following MI. We then conducted ac4C-RNA binding protein immunoprecipitation-sequencing (RIP-seq) in cardiac fibroblasts transfected with Nat10 siRNA, and revealed that angiomotin-like 1 (Amotl1), an upstream regulator of the Hippo signaling pathway, was the target gene of Nat10. We demonstrated that Nat10-mediated ac4C modification of Amotl1 increased its mRNA stability and translation in neonatal cardiac fibroblasts, thereby increasing the interaction of Amotl1 with yes-associated protein 1 (Yap) and facilitating Yap translocation into the nucleus. Intriguingly, silencing of Amotl1 or Yap, as well as treatment with verteporfin, a selective and potent Yap inhibitor, attenuated the Nat10 overexpression-induced proliferation of cardiac fibroblasts and prevented their differentiation into myofibroblasts in vitro. In conclusion, this study highlights Nat10 as a crucial regulator of myocardial fibrosis following MI injury through ac4C modification of upstream activators within the Hippo/Yap signaling pathway.

Remodelin delays non-small cell lung cancer progression by inhibiting NAT10 via the EMT pathway.

BACKGROUND: Lung cancer remains the foremost reason of cancer-related mortality, with invasion and metastasis profoundly influencing patient prognosis. N-acetyltransferase 10 (NAT10) catalyzes the exclusive N (4)-acetylcytidine (ac4C) modification in eukaryotic RNA. NAT10 dysregulation is linked to various diseases, yet its role in non-small cell lung cancer (NSCLC) invasion and metastasis remains unclear. Our study delves into the clinical significance and functional aspects of NAT10 in NSCLC. METHODS: We investigated NAT10's clinical relevance using The Cancer Genome Atlas (TCGA) and a group of 98 NSCLC patients. Employing WB, qRT-PCR, and IHC analyses, we assessed NAT10 expression in NSCLC tissues, bronchial epithelial cells (BECs), NSCLC cell lines, and mouse xenografts. Further, knockdown and overexpression techniques (siRNA, shRNA, and plasmid) were employed to evaluate NAT10's effects. A series of assays were carried out, including CCK-8, colony formation, wound healing, and transwell assays, to elucidate NAT10's role in proliferation, invasion, and metastasis. Additionally, we utilized lung cancer patient-derived 3D organoids, mouse xenograft models, and Remodelin (NAT10 inhibitor) to corroborate these findings. RESULTS: Our investigations revealed high NAT10 expression in NSCLC tissues, cell lines and mouse xenograft models. High NAT10 level correlated with advanced T stage, lymph node metastasis and poor overall survive. NAT10 knockdown curtailed proliferation, invasion, and migration, whereas NAT10 overexpression yielded contrary effects. Furthermore, diminished NAT10 levels correlated with increased E-cadherin level whereas decreased N-cadherin and vimentin expressions, while heightened NAT10 expression displayed contrasting results. Notably, Remodelin efficiently attenuated NSCLC proliferation, invasion, and migration by inhibiting NAT10 through the epithelial-mesenchymal transition (EMT) pathway. CONCLUSIONS: Our data underscore NAT10 as a potential therapeutic target for NSCLC, presenting avenues for targeted intervention against lung cancer through NAT10 inhibition.

Evaluating possible maternal effect lethality and genetic background effects in Naa10 knockout mice.

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/y male mice on the inbred genetic background in this different animal facility.

NAA10 gene related Ogden syndrome with obstructive hypertrophic cardiomyopathy: A rare case report.

RATIONALE: Ogden syndrome is an exceptionally rare X-linked disease caused by mutations in the NAA10 gene. Reported cases of this syndrome are approximately 20 children and are associated with facial dysmorphism, growth delay, developmental disorders, congenital heart disease, and arrhythmia. PATIENT CONCERNS: We present the clinical profile of a 3-year-old girl with Ogden syndrome carrying a de novo NAA10 variant [NM_003491:c.247C>T, p.(Arg83Cys)]. During infancy, she exhibited features such as left ventricular hypertrophy, protruding eyeballs, and facial deformities. DIAGNOSIS: Clinical diagnosis included Ogden syndrome, congenital heart disease (obstructive hypertrophic cardiomyopathy, left ventricular outflow tract obstruction, mitral valve disease, tricuspid valve regurgitation), tonsillar and adenoidal hypertrophy, and speech and language delay. INTERVENTIONS: The girl was considered to have hypertrophic cardiomyopathy (HCM) and received oral metoprolol as a treatment for HCM at our hospital. The drug treatment effect was not ideal, and her hypertrophy myocardial symptoms were aggravated and she had to be hospitalized for surgery. OUTCOMES: The girl underwent a modified Morrow procedure under cardiopulmonary bypass and experienced a favorable postoperative recovery. No pulmonary infections or significant complications were observed during this period. The patient's family expressed satisfaction with the treatment process. LESSONS: The case emphasizes the HCM of Odgen syndrome, and early surgery should be performed if drug treatment is ineffective.

NAA10 gene expression is associated with mesenchymal transition, dedifferentiation, and progression of clear cell renal cell carcinoma.

INTRODUCTION: We aimed to investigate the expression and prognostic role of NAA10 in clear cell renal cell carcinoma (ccRCC). MATERIAL AND METHODS: We performed a gene expression and survival analysis based on the human cancer genome atlas database of ccRCC patients (TCGA-KIRC). RESULTS: The patients in the TCGA-KIRC (n = 537) were divided into two subgroups: NAA10-low and NAA10-high expression groups. NAA10-high ccRCC exhibited higher T stages (p = 0.002), a higher frequency of distant metastasis (p = 0.018), more advanced AJCC stages (p < 0.001), a lower overall survival time (p = 0.036), and a lower survival rate (p < 0.001). NAA10-high ccRCC was associated with increased activity of non-specific oncogenic pathways, including oxidative phosphorylation (p < 0.001) and cell cycle progression [G2 to M phase transition (p = 0.045) and E2F targets (p < 0.001)]. Additionally, the NAA10-high tumors showed reduced apoptosis via TRIAL pathways (p < 0.001) and increased levels of activity that promoted epithelial-mesenchymal transition (p = 0.026) or undifferentiation (p = 0.01). In ccRCC, NAA10 expression was found to be a negative prognostic factor in both non-metastatic (p < 0.001) and metastatic tumors (p = 0.032). CONCLUSIONS: In ccRCC, NAA10 expression was shown to be a negative prognostic factor related to tumor progression rather than tumor initiation, and high NAA10 expression promoted epithelial-mesenchymal transition and undifferentiation.

The mechanistic role of NAT10 in cancer: Unraveling the enigmatic web of oncogenic signaling.

N-acetyltransferase 10 (NAT10), a versatile enzyme, has gained considerable attention as a significant player in the complex realm of cancer biology. Its enigmatic role in tumorigenesis extends across a wide array of cellular processes, impacting cell growth, differentiation, survival, and genomic stability. Within the intricate network of oncogenic signaling, NAT10 emerges as a crucial agent in multiple cancer types, such as breast, lung, colorectal, and leukemia. This compelling research addresses the intricate complexity of the mechanistic role of NAT10 in cancer development. By elucidating its active participation in essential physiological processes, we investigate the regulatory role of NAT10 in cell cycle checkpoints, coordination of chromatin remodeling, and detailed modulation of the delicate balance between apoptosis and cell survival. Perturbations in NAT10 expression and function have been linked to oncogenesis, metastasis, and drug resistance in a variety of cancer types. Furthermore, the bewildering interactions between NAT10 and key oncogenic factors, such as p53 and c-Myc, are deciphered, providing profound insights into the molecular underpinnings of cancer pathogenesis. Equally intriguing, the paradoxical role of NAT10 as a potential tumor suppressor or oncogene is influenced by context-dependent factors and the cellular microenvironment. This study explores the fascinating interplay of genetic changes, epigenetic changes, and post-translational modifications that shape the dual character of NAT10, revealing the delicate balance between cancer initiation and suppression. Taken together, this overview delves deeply into the enigmatic role of NAT10 in cancer, elucidating its multifaceted roles and its complex interplay with oncogenic networks.

Multiple impacts of Naa10p on cancer progression: Molecular functions and clinical prospects.

Nα-acetyltransferase 10 protein (Naa10p) is known as the catalytic subunit of N-terminal acetyltransferases A (NatA) complex, associating with Naa15p to acetylate N-termini of the human proteome. Recent investigations have unveiled additional functions for Naa10p, encompassing lysine ε-acetylation and acetyltransferase-independent activities. Its pleiotropic roles have been implicated in diverse physiological and pathological contexts. Emerging evidence has implicated Naa10p in cancer progression, demonstrating dual attributes as an oncogene or a tumor suppressor contingent on the cancer type and acetyltransferase activity context. In this comprehensive review, we present a pan-cancer analysis aimed at elucidating the intricacies underlying Naa10p dysregulation in cancer. Our findings propose the potential involvement of c-Myc as a modulatory factor influencing Naa10p expression. Moreover, we provide a consolidated summary of recent advancements in understanding the intricate molecular underpinnings through which Naa10p contributes to cancer cell proliferation and metastasis. Furthermore, we delve into the multifaceted nature of Naa10p's roles in regulating cancer behaviors, potentially attributed to its interactions with a repertoire of partner proteins. Through an exhaustive exploration of Naa10p's functions, spanning its acetylation activity and acetyltransferase-independent functionalities, this review offers novel insights with implications for targeted therapeutic strategies involving this pivotal protein in the realm of cancer therapeutics.

Loss of N-terminal acetyltransferase A activity induces thermally unstable ribosomal proteins and increases their turnover in Saccharomyces cerevisiae.

Protein N-terminal (Nt) acetylation is one of the most abundant modifications in eukaryotes, covering ~50-80 % of the proteome, depending on species. Cells with defective Nt-acetylation display a wide array of phenotypes such as impaired growth, mating defects and increased stress sensitivity. However, the pleiotropic nature of these effects has hampered our understanding of the functional impact of protein Nt-acetylation. The main enzyme responsible for Nt-acetylation throughout the eukaryotic kingdom is the N-terminal acetyltransferase NatA. Here we employ a multi-dimensional proteomics approach to analyze Saccharomyces cerevisiae lacking NatA activity, which causes global proteome remodeling. Pulsed-SILAC experiments reveals that NatA-deficient strains consistently increase degradation of ribosomal proteins compared to wild type. Explaining this phenomenon, thermal proteome profiling uncovers decreased thermostability of ribosomes in NatA-knockouts. Our data are in agreement with a role for Nt-acetylation in promoting stability for parts of the proteome by enhancing the avidity of protein-protein interactions and folding.

Expanding the phenotypic spectrum of NAA10-related neurodevelopmental syndrome and NAA15-related neurodevelopmental syndrome.

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting 80% of cytosolic proteins in humans. The human essential gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex, also including the accessory protein, NAA15. The full spectrum of human genetic variation in this pathway is currently unknown. Here we reveal the genetic landscape of variation in NAA10 and NAA15 in humans. Through a genotype-first approach, one clinician interviewed the parents of 56 individuals with NAA10 variants and 19 individuals with NAA15 variants, which were added to all known cases (N = 106 for NAA10 and N = 66 for NAA15). Although there is clinical overlap between the two syndromes, functional assessment demonstrates that the overall level of functioning for the probands with NAA10 variants is significantly lower than the probands with NAA15 variants. The phenotypic spectrum includes variable levels of intellectual disability, delayed milestones, autism spectrum disorder, craniofacial dysmorphology, cardiac anomalies, seizures, and visual abnormalities (including cortical visual impairment and microphthalmia). One female with the p.Arg83Cys variant and one female with an NAA15 frameshift variant both have microphthalmia. The frameshift variants located toward the C-terminal end of NAA10 have much less impact on overall functioning, whereas the females with the p.Arg83Cys missense in NAA10 have substantial impairment. The overall data are consistent with a phenotypic spectrum for these alleles, involving multiple organ systems, thus revealing the widespread effect of alterations of the NTA pathway in humans.

NAA10 overexpression dictates distinct epigenetic, genetic, and clinicopathological characteristics in adult gliomas.

NAA10 is a novel biomarker of cancer progression. The oncogenic and biological mechanisms of NAA10 in human malignancies are controversial and remain to be elucidated. Herein, we investigated the biological and clinicopathological implications of NAA10 gene expression in adult gliomas. We collected data from The Human Cancer Genome Atlas (TCGA) database, including patients from TCGA-GBM and TCGA-LGG projects. In total, there were 666 patients from the 2 projects (513 and 153 from TCGA-LGG and TCGA-GBM, respectively). Different analyses (pathway, DNA methylation, and survival analyses) require further specific case eliminations. Based on NAA10 expression, we divided 666 tumors into 2 subgroups: NAA10-high and NAA10-low glioma. There were higher activities of cell proliferation, metabolic reprogramming, DNA repair, angiogenesis, epithelial-mesenchymal transition, TNF-α, IL6/JAK/STAT6, mTORC1 signaling, and MYC targets in NAA10-high glioma, while P53, TGF-ß, Wnt, and Hedgehog pathways were highly expressed by NAA10-low gliomas. t-distributed stochastic neighbors embedding dimension reduction of DNA methylation also showed a high distribution of NAA10-high gliomas in distinct clusters. Survival analyses showed that high NAA10 expression was an independent prognostic factor. NAA10 expression dictated epigenetic, genetic, and clinicopathological differences in adult glioma. Further studies are required to investigate the detailed NAA10 oncogenic mechanisms and to validate NAA10 immunohistochemistry.

Phenotypic variability and gastrointestinal manifestations/interventions for growth in NAA10-related neurodevelopmental syndrome.

Our study of 61 children with NAA10-related neurodevelopmental syndrome, an X-linked disorder due to NAA10 gene variants, demonstrated a high prevalence of growth failure, with weight and height percentiles often in the failure-to-thrive diagnostic range; however, dramatic weight fluctuations and phenotypic variability is evidenced in the growth parameters of this population. Although never previously explored in depth, the gastrointestinal pathology associated with NAA10-related neurodevelopmental syndrome includes feeding difficulties in infancy, dysphagia, GERD/silent reflux, vomiting, constipation, diarrhea, bowel incontinence, and presence of eosinophils on esophageal endoscopy, in order from most to least prevalent. Additionally, the gastrointestinal symptom profile for children with this syndrome has been expanded to include eosinophilic esophagitis, cyclic vomiting syndrome, Mallory Weiss tears, abdominal migraine, esophageal dilation, and subglottic stenosis. Although the exact cause of poor growth in NAA10-related neurodevelopmental syndrome probands is unclear and the degree of contribution to this problem by GI symptomatology remains uncertain, an analysis including nine G-tube or GJ-tube fed probands demonstrates that G/GJ-tubes are overall efficacious with respect to improvements in weight gain and caregiving. The choice to insert a gastrostomy or gastrojejunal tube to aid with weight gain is often a challenging decision to make for parents, who may alternatively choose to rely on oral feeding, caloric supplementation, calorie tracking, and feeding therapy. In this case, if NAA10-related neurodevelopmental syndrome children are not tracking above the failure to thrive (FTT) range past 1 year of age despite such efforts, the treating physicians should be consulted regarding possibly undergoing G-tube placement to avoid prolonged growth failure. If G-tubes are not immediately inducing weight gain after insertion, recommendations could include altering formula, increasing caloric input, or exchanging a G-tube for a GJ-tube by means of a minimally invasive procedure.

Exosomal circ_0026611 contributes to lymphangiogenesis by reducing PROX1 acetylation and ubiquitination in human lymphatic endothelial cells (HLECs).

BACKGROUND: Esophageal squamous carcinoma (ESCC) is a common malignancy that originates in the digestive tract. Lymph node metastasis (LNM) is a complicated process, and tumor lymphangiogenesis has been reported to be associated with the spread of tumor cells to lymph nodes (LNs), including in ESCC. However, little is currently known about the mechanisms involved in lymphangiogenesis in ESCC tumors. According to previous literature, we know that hsa_circ_0026611 expresses at a high level in serum exosomes of patients with ESCC and shows a close association with LNM and poor prognosis. However, details on the functions of circ_0026611 in ESCC remain unclear. We aim to explore the effects of circ_0026611 in ESCC cell-derived exosomes on lymphangiogenesis and its potential molecular mechanism. METHODS: We firstly examined how circ_0026611 may express in ESCC cells and exosomes by quantitative reverse transcription real-time polymerase chain reaction (RT-qPCR). The potential effects circ_0026611 may exert on lymphangiogenesis in ESCC cell-derived exosomes were assessed afterward via mechanism experiments. RESULTS: circ_0026611 high expression pattern was confirmed in ESCC cells and exosomes. ESCC cell-derived exosomes promoted lymphangiogenesis by transferring circ_0026611. Besides, circ_0026611 interacted with N-α-acetyltransferase 10 (NAA10) to inhibit NAA10-mediated prospero homeobox 1 (PROX1) acetylation with subsequent ubiquitination and degradation. Furthermore, circ_0026611 was verified to promote lymphangiogenesis in a PROX1-mediated manner. CONCLUSIONS: Exosomal circ_0026611 inhibited PROX1 acetylation and ubiquitination to promote lymphangiogenesis in ESCC.

Expanded in vivo substrate profile of the yeast N-terminal acetyltransferase NatC.

N-terminal acetylation is a conserved protein modification among eukaryotes. The yeast Saccharomyces cerevisiae is a valuable model system for studying this modification. The bulk of protein N-terminal acetylation in S. cerevisiae is catalyzed by the N-terminal acetyltransferases NatA, NatB, and NatC. Thus far, proteome-wide identification of the in vivo protein substrates of yeast NatA and NatB has been performed by N-terminomics. Here, we used S. cerevisiae deleted for the NatC catalytic subunit Naa30 and identified 57 yeast NatC substrates by N-terminal combined fractional diagonal chromatography analysis. Interestingly, in addition to the canonical N-termini starting with ML, MI, MF, and MW, yeast NatC substrates also included MY, MK, MM, MA, MV, and MS. However, for some of these substrate types, such as MY, MK, MV, and MS, we also uncovered (residual) non-NatC NAT activity, most likely due to the previously established redundancy between yeast NatC and NatE/Naa50. Thus, we have revealed a complex interplay between different NATs in targeting methionine-starting N-termini in yeast. Furthermore, our results showed that ectopic expression of human NAA30 rescued known NatC phenotypes in naa30Δ yeast, as well as partially restored the yeast NatC Nt-acetylome. Thus, we demonstrate an evolutionary conservation of NatC from yeast to human thereby underpinning future disease models to study pathogenic NAA30 variants. Overall, this work offers increased biochemical and functional insights into NatC-mediated N-terminal acetylation and provides a basis for future work to pinpoint the specific molecular mechanisms that link the lack of NatC-mediated N-terminal acetylation to phenotypes of NatC deletion yeast.

Naa10p promotes cell invasiveness of esophageal cancer by coordinating the c-Myc and PAI1 regulatory axis.

N-α-acetyltransferase 10 protein, Naa10p, is involved in various cellular functions impacting tumor progression. Due to its capacity to acetylate a large spectrum of proteins, both oncogenic and tumor-suppressive roles of Naa10p have been documented. Here, we report an oncogenic role of Naa10p in promoting metastasis of esophageal cancer. NAA10 is more highly expressed in esophageal cancer tissues compared to normal tissues. Higher NAA10 expression also correlates with poorer survival of esophageal cancer patients. We found that NAA10 expression was transcriptionally regulated by the critical oncogene c-Myc in esophageal cancer. Furthermore, activation of the c-Myc-Naa10p axis resulted in upregulated cell invasiveness of esophageal cancer. This increased cell invasiveness was also elucidated to depend on the enzymatic activity of Naa10p. Moreover, Naa10p cooperated with Naa15p to interact with the protease inhibitor, PAI1, and prevent its secretion. This inhibition of PAI1 secretion may derive from the N-terminal acetylation effect of the Naa10p/Naa15p complex. Our results establish the significance of Naa10p in driving metastasis in esophageal cancer by coordinating the c-Myc-PAI1 axis, with implications for its potential use as a prognostic biomarker and therapeutic target for esophageal cancer.