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1.
Medicine (Baltimore) ; 103(6): e36034, 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38335407

RESUMO

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.


Assuntos
Cardiomiopatia Hipertrófica , Cardiopatias Congênitas , Humanos , Feminino , Criança , Pré-Escolar , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/diagnóstico , Valva Mitral , Miocárdio , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/genética , Hipertrofia , Acetiltransferase N-Terminal A , Acetiltransferase N-Terminal E
2.
Pathol Res Pract ; 255: 155191, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38340582

RESUMO

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.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Prognóstico , Transição Epitelial-Mesenquimal/genética , Expressão Gênica , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal E/genética
3.
Pathol Res Pract ; 253: 154990, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38056132

RESUMO

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.


Assuntos
Acetiltransferases N-Terminal , Neoplasias , Humanos , Acetiltransferases N-Terminal/genética , Acetiltransferases N-Terminal/metabolismo , Acetiltransferase N-Terminal E/genética , Acetiltransferase N-Terminal E/metabolismo , Neoplasias/genética , Processamento de Proteína Pós-Traducional , Microambiente Tumoral
6.
Biochim Biophys Acta Rev Cancer ; 1878(6): 188973, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37659460

RESUMO

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.


Assuntos
Acetiltransferases , Neoplasias , Humanos , Acetiltransferases/genética , Acetiltransferases/metabolismo , Acetiltransferase N-Terminal E/genética , Acetiltransferase N-Terminal E/metabolismo , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal A/metabolismo , Processamento de Proteína Pós-Traducional , Neoplasias/tratamento farmacológico , Neoplasias/genética
7.
Nat Commun ; 14(1): 4517, 2023 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-37500638

RESUMO

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.


Assuntos
Acetiltransferases N-Terminal , Proteínas de Saccharomyces cerevisiae , Acetiltransferases N-Terminal/genética , Acetiltransferases N-Terminal/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Acetiltransferase N-Terminal A/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteoma/metabolismo , Acetilação , Acetiltransferases/genética , Acetiltransferases/metabolismo , Acetiltransferase N-Terminal E/metabolismo
8.
Eur J Hum Genet ; 31(7): 824-833, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37130971

RESUMO

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.


Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Microftalmia , Humanos , Feminino , Síndrome , Acetiltransferase N-Terminal E/genética , Acetiltransferase N-Terminal E/metabolismo , Genótipo , Deficiência Intelectual/genética , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal A/metabolismo
9.
J Neuropathol Exp Neurol ; 82(7): 650-658, 2023 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-37253389

RESUMO

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.


Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Adulto , Neoplasias Encefálicas/patologia , Proteínas Hedgehog/genética , Glioma/patologia , Metilação de DNA , Epigênese Genética , Prognóstico , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal A/metabolismo , Acetiltransferase N-Terminal E/genética , Acetiltransferase N-Terminal E/metabolismo
10.
Cell Mol Biol Lett ; 28(1): 13, 2023 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-36803975

RESUMO

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.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , MicroRNAs , RNA Circular , Humanos , Acetilação , Linhagem Celular Tumoral , Proliferação de Células , Células Endoteliais/metabolismo , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Linfangiogênese/genética , Metástase Linfática , MicroRNAs/metabolismo , Acetiltransferase N-Terminal A/metabolismo , Acetiltransferase N-Terminal E/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitinação , RNA Circular/genética
11.
Am J Med Genet A ; 191(5): 1293-1300, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36810866

RESUMO

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.


Assuntos
Nutrição Enteral , Refluxo Gastroesofágico , Criança , Humanos , Nutrição Enteral/métodos , Gastrostomia/métodos , Refluxo Gastroesofágico/cirurgia , Síndrome , Insuficiência de Crescimento/genética , Aumento de Peso , Variação Biológica da População , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal E
12.
J Biol Chem ; 299(2): 102824, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36567016

RESUMO

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.


Assuntos
Acetiltransferases N-Terminal , Saccharomyces cerevisiae , Humanos , Acetilação , Cromatografia Líquida , Sequência Conservada , Teste de Complementação Genética , Metionina/metabolismo , Acetiltransferase N-Terminal C/genética , Acetiltransferase N-Terminal C/metabolismo , Acetiltransferase N-Terminal E , Acetiltransferases N-Terminal/deficiência , Acetiltransferases N-Terminal/genética , Acetiltransferases N-Terminal/metabolismo , Fenótipo , Processamento de Proteína Pós-Traducional , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/metabolismo , Especificidade por Substrato
13.
Cell Death Dis ; 13(11): 995, 2022 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-36433943

RESUMO

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.


Assuntos
Neoplasias Esofágicas , Humanos , Acetilação , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/fisiopatologia , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal A/metabolismo , Acetiltransferase N-Terminal E/genética , Acetiltransferase N-Terminal E/metabolismo
16.
Int J Mol Sci ; 23(18)2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36142717

RESUMO

Most eukaryotic proteins are N-terminally acetylated by a set of Nα acetyltransferases (NATs). This ancient and ubiquitous modification plays a fundamental role in protein homeostasis, while mutations are linked to human diseases and phenotypic defects. In particular, Naa50 features species-specific differences, as it is inactive in yeast but active in higher eukaryotes. Together with NatA, it engages in NatE complex formation for cotranslational acetylation. Here, we report Naa50 homologs from the filamentous fungi Chaetomium thermophilum and Neurospora crassa with significant N- and C-terminal extensions to the conserved GNAT domain. Structural and biochemical analyses show that CtNaa50 shares the GNAT structure and substrate specificity with other homologs. However, in contrast to previously analyzed Naa50 proteins, it does not form NatE. The elongated N-terminus increases Naa50 thermostability and binds to dynein light chain protein 1, while our data suggest that conserved positive patches in the C-terminus allow for ribosome binding independent of NatA. Our study provides new insights into the many facets of Naa50 and highlights the diversification of NATs during evolution.


Assuntos
Acetiltransferase N-Terminal E , Acetiltransferases N-Terminal , Acetilação , Acetiltransferases/metabolismo , Dineínas/metabolismo , Humanos , Acetiltransferase N-Terminal E/química , Acetiltransferases N-Terminal/metabolismo , Saccharomyces cerevisiae/metabolismo
17.
Biomed Res Int ; 2022: 2449449, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35669725

RESUMO

Background: Bladder cancer (BLCA) is one of the most common urological malignancies globally, posing a severe threat to public health. In combination with protein-protein interaction (PPI) network analysis of proteomics, Gene Set Variation Analysis (GSVA) and "CancerSubtypes" package of R software for transcriptomics can help identify biomarkers related to BLCA prognosis. This will have significant implications for prevention and treatment. Method: BLCA data were downloaded from The Cancer Genome Atlas (TCGA) database and GEO database (GSE13507). GSVA analysis converted the gene expression matrix to the gene set expression matrix. "CancerSubtypes" classified patients into three subtypes and established a prognostic model based on differentially expressed gene sets (DEGSs) among the three subtypes. For genes from prognosis-related DEGSs, functional and pathway enrichment analyses and PPI network analysis were carried out. The Human Protein Atlas (HPA) database was used for validation. Finally, the proportion of tumor-infiltrating immune cells (TIICs) was determined using the CIBERSORT algorithm. Results: In total, 414 tumor samples and 19 adjacent-tumor samples were obtained from TCGA, with 145 samples belonging to subtype A, 126 samples belonging to subtype B, and 136 samples belonging to subtype C. Then, we identified 83 DEGSs and constituted a prognostic signature with two of them: "GSE1460_CD4_THYMOCYTE_VS_THYMIC_STROMAL_CELL_DN" and "MODULE_253." Finally, five subnets of two PPI networks were established, and nine core proteins were obtained: CDH2, COL1A1, EIF2S2, PSMA3, NAA10, DNM1L, TUBA4A, KIF11, and KIF23. The HPA database confirmed the expression of the nine core proteins in BLCA tissues. Furthermore, EIF2S2, PSMA3, DNM1L, and TUBA4A could be novel BLCA prognostic biomarkers. Conclusions: In this study, we discovered two gene sets linked to BLCA prognosis. PPI analysis confirmed the network's core proteins, and several newly discovered biomarkers of BLCA prognosis were identified.


Assuntos
Neoplasias da Bexiga Urinária , Biomarcadores Tumorais/genética , Bases de Dados de Proteínas , Humanos , Acetiltransferase N-Terminal A , Acetiltransferase N-Terminal E , Prognóstico , Mapas de Interação de Proteínas/genética , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/patologia
18.
Sci Adv ; 8(24): eabn6153, 2022 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-35704578

RESUMO

In humans, the Huntingtin yeast partner K (HYPK) binds to the ribosome-associated Nα-acetyltransferase A (NatA) complex that acetylates ~40% of the proteome in humans and Arabidopsis thaliana. However, the relevance of HsHYPK for determining the human N-acetylome is unclear. Here, we identify the AtHYPK protein as the first in vivo regulator of NatA activity in plants. AtHYPK physically interacts with the ribosome-anchoring subunit of NatA and promotes Nα-terminal acetylation of diverse NatA substrates. Loss-of-AtHYPK mutants are remarkably resistant to drought stress and strongly resemble the phenotype of NatA-depleted plants. The ectopic expression of HsHYPK rescues this phenotype. Combined transcriptomics, proteomics, and N-terminomics unravel that HYPK impairs plant metabolism and development, predominantly by regulating NatA activity. We demonstrate that HYPK is a critical regulator of global proteostasis by facilitating masking of the recently identified nonAc-X2/N-degron. This N-degron targets many nonacetylated NatA substrates for degradation by the ubiquitin-proteasome system.


Assuntos
Arabidopsis , Acetiltransferase N-Terminal A , Acetilação , Acetiltransferases/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal A/metabolismo , Acetiltransferase N-Terminal E/genética , Acetiltransferase N-Terminal E/metabolismo , Proteostase
20.
J Cell Mol Med ; 26(10): 2921-2934, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35366056

RESUMO

N-α-Acetyltransferase 10 (NAA10) was reported to be involved in tumour invasion and metastasis in several of tumours. However, the role and mechanism of NAA10-mediated invasion and metastasis in oral squamous cell carcinoma (OSCC) remains undetermined. Herein, our study showed that NAA10 inhibits cell migration and invasion in vitro and attenuates the xenograft tumorigenesis in nude mice. Mechanistically, we demonstrated that there is a physical interaction between NAA10 and RelA/p65 in OSCC cells, thereby preventing RelA/p65-mediated transcriptional activation of Pirh2. Consequently, inhibition of Pirh2 increased p53 level and suppressed the expression of p53 downstream targets, matrix metalloprotein-2 (MMP-2) and MMP-9. Therefore, NAA10 may function as a tumour metastasis suppressor in the progression of OSCC by targeting Pirh2-p53 axis and might be a prognostic marker as well as a therapeutic target for OSCC.


Assuntos
Neoplasias Bucais , Acetiltransferase N-Terminal A , Acetiltransferase N-Terminal E , Carcinoma de Células Escamosas de Cabeça e Pescoço , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Nus , Neoplasias Bucais/patologia , Acetiltransferase N-Terminal A/metabolismo , Acetiltransferase N-Terminal E/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases
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