Lysine 2-hydroxyisobutyrylation of NAT10 promotes cancer metastasis in an ac4C-dependent manner

Liao, Long; He, Yan; Li, Shujun; Yu, Xiaomei; Liu, Zhi-Chao; Liang, Yiyao; Han, Yu; Yang, Jing; Zhang, Guo-Geng; Deng, Chun-Miao; Xian, Wa; Zhu, Yifei; Xu, Tao-Yang; Zheng, Can‐Can; Cheng, Chao; Li, Ang; Li, Zhigang; Liu, Jin-Bao; Li, Bin

doi:10.1038/s41422-023-00793-4

Cited by 54 publications

(34 citation statements)

References 43 publications

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“…35 Notably, research indicated that the mutation of K823 to R significantly impaired the protein stability of NAT10. 7 In this research, our focus was on exploring the impact of Khib on the functionality of Grx. Grx, a small and evolutionarily conserved redox protein, is widely distributed in plants and serves as a critical component of the plant antioxidant system.…”

Section: ■ Discussionmentioning

confidence: 99%

“…In the context of Khib, the presence of this modification at the K260 site in ALDH1A1 was found to decrease both its enzyme activity and protein stability in bladder cancer . Notably, research indicated that the mutation of K823 to R significantly impaired the protein stability of NAT10 . In this research, our focus was on exploring the impact of Khib on the functionality of Grx.…”

Section: Discussionmentioning

confidence: 99%

“…An accumulating body of evidence now confirms that the crosstalk among various PTMs has been known to play a crucial role in modulating protein function. 7,11 To determine the existence of a crosstalk of Khib with the other acylations in Syn7002, we performed a comparative analysis of 2hydroxyisobutyrylome alongside the previously published a c e t y l o m e , s u c c i n y l o m e , a n d p r o p i o n y l o m e i n Syn7002. 19,20,41 Our analysis revealed a potential crosstalk between Khib and the other PTMs, including Kac, Ksu, and Kpr in Syn7002 (Figure 5A and Table S10A).…”

Section: Correlation Between Khib and Other Acylationsmentioning

confidence: 99%

“…It was initially identified in human and mouse histones, and H4K8hib was observed to be associated with gene transcription in male sperm meiotic cells . Recently, Khib has been reported in a number of eukaryotic and prokaryotic histones and nonhistone proteins, which have been widely implicated in diverse biological processes, including cellular transcription, energy metabolism, myocardial hypertrophy, and cancer metastasis. − In plants and bacteria, Khib could play important roles in stress responses. − These previous reports demonstrate that Khib occurs in a large number of proteins and influences diverse biological functions in all domains of life.…”

Section: Introductionmentioning

confidence: 99%

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Identification and Functional Analysis of Lysine 2-Hydroxyisobutyrylation in Cyanobacteria

Li,

Lin,

et al. 2024

J. Proteome Res.

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Cyanobacteria are the oldest prokaryotic photoautotrophic microorganisms and have evolved complicated post-translational modification (PTM) machinery to respond to environmental stress. Lysine 2-hydroxyisobutyrylation (Khib) is a newly identified PTM that is reported to play important roles in diverse biological processes, however, its distribution and function in cyanobacteria have not been reported. Here, we performed the first systematic studies of Khib in a model cyanobacterium Synechococcus sp. strain PCC 7002 (Syn7002) using peptide prefractionation, pan-Khib antibody enrichment, and high-accuracy mass spectrometry (MS) analysis. A total of 1875 highconfidence Khib sites on 618 proteins were identified, and a large proportion of Khib sites are present on proteins in the cellular metabolism, protein synthesis, and photosynthesis pathways. Using sitedirected mutagenesis and functional studies, we showed that Khib of glutaredoxin (Grx) affects the efficiency of the PS II reaction center and H 2 O 2 resistance in Syn7002. Together, this study provides novel insights into the functions of Khib in cyanobacteria and suggests that reversible Khib may influence the stress response and photosynthesis in both cyanobacteria and plants.

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Section: ■ Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Correlation Between Khib and Other Acylationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification and Functional Analysis of Lysine 2-Hydroxyisobutyrylation in Cyanobacteria

Li,

Lin,

et al. 2024

J. Proteome Res.

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“…Remarkably, ac 4 C (position 34) modification of tRNA Met is formed through an acetate ion without acetyltransferases . Dysregulation of NAT10 and abnormal ac 4 C acetylation have been found to be associated with diverse diseases, including cancers and premature aging syndromes. − It is therefore important to detect ac 4 C to elucidate how epitranscriptomic metabolism affects cellular physiology and may allow us to develop new therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

Antibody-Free Fluorine-Assisted Metabolic Sequencing of RNA N⁴-Acetylcytidine

Yan,

Lu,

Yang

et al. 2023

J. Am. Chem. Soc.

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N 4 -Acetylcytidine (ac 4 C) has been found to affect a variety of cellular and biological processes. For a mechanistic understanding of the roles of ac 4 C in biology and disease, we present an antibody-free, fluorine-assisted metabolic sequencing method to detect RNA ac 4 C, called "FAM-seq". We successfully applied FAM-seq to profile ac 4 C landscapes in human 293T, HeLa, and MDA cell lines in parallel with the reported acRIP-seq method. By comparison with the classic ac 4 C antibody sequencing method, we found that FAM-seq is a convenient and reliable method for transcriptome-wide mapping of ac 4 C. Because this method holds promise for detecting nascent RNA ac 4 C modifications, we further investigated the role of ac 4 C in regulating chemotherapy drug resistance in chronic myeloid leukemia. The results indicated that drug development or combination therapy could be enhanced by appreciating the key role of ac 4 C modification in cancer therapy.

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Targeting N4‐acetylcytidine suppresses hepatocellular carcinoma progression by repressing eEF2‐mediated HMGB2 mRNA translation

Liu,

Xu,

Yue

et al. 2024

Cancer Communications

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BackgroundN4‐acetylcytidine (ac4C) represents a novel messenger RNA (mRNA) modification, and its associated acetyltransferase N‐acetyltransferase 10 (NAT10) plays a crucial role in the initiation and progression of tumors by regulating mRNA functionality. However, its role in hepatocellular carcinoma (HCC) development and prognosis is largely unknown. This study aimed to elucidate the role of NAT10‐mediated ac4C in HCC progression and provide a promising therapeutic approach.MethodsThe ac4C levels were evaluated by dot blot and ultra‐performance liquid chromatography‐tandem mass spectrometry with harvested HCC tissues. The expression of NAT10 was investigated using quantitative real‐time polymerase chain reaction, western blotting, and immunohistochemical staining across 91 cohorts of HCC patients. To explore the underlying mechanisms of NAT10‐ac4C in HCC, we employed a comprehensive approach integrating acetylated RNA immunoprecipitation and sequencing, RNA sequencing and ribosome profiling analyses, along with RNA immunoprecipitation, RNA pull‐down, mass spectrometry, and site‐specific mutation analyses. The drug affinity responsive targets stability, cellular thermal shift assay, and surface plasmon resonance assays were performed to assess the specific binding of NAT10 and Panobinostat. Furthermore, the efficacy of targeting NAT10‐ac4C for HCC treatment was elucidated through in vitro experiments using HCC cells and in vivo HCC mouse models.ResultsOur investigation revealed a significant increase in both the ac4C RNA level and NAT10 expression in HCC. Notably, elevated NAT10 expression was associated with poor outcomes in HCC patients. Functionally, silencing NAT10 suppressed HCC proliferation and metastasis in vitro and in vivo. Mechanistically, NAT10 stimulates the ac4C modification within the coding sequence (CDS) of high mobility group protein B2 (HMGB2), which subsequently enhances HMGB2 translation by facilitating eukaryotic elongation factor 2 (eEF2) binding to the ac4C sites on HMGB2 mRNA's CDS. Additionally, high‐throughput compound library screening revealed Panobinostat as a potent inhibitor of NAT10‐mediated ac4C modification. This inhibition significantly attenuated HCC growth and metastasis in both in vitro experiments using HCC cells and in vivo HCC mouse models.ConclusionsOur study identified a novel oncogenic epi‐transcriptome axis involving NAT10‐ac4C/eEF2‐HMGB2, which plays a pivotal role in regulating HCC growth and metastasis. The drug Panobinostat validates the therapeutic potential of targeting this axis for HCC treatment.

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Lysine 2-hydroxyisobutyrylation of NAT10 promotes cancer metastasis in an ac4C-dependent manner

Cited by 54 publications

References 43 publications

Identification and Functional Analysis of Lysine 2-Hydroxyisobutyrylation in Cyanobacteria

Identification and Functional Analysis of Lysine 2-Hydroxyisobutyrylation in Cyanobacteria

Antibody-Free Fluorine-Assisted Metabolic Sequencing of RNA N⁴-Acetylcytidine

Targeting N4‐acetylcytidine suppresses hepatocellular carcinoma progression by repressing eEF2‐mediated HMGB2 mRNA translation

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Lysine 2-hydroxyisobutyrylation of NAT10 promotes cancer metastasis in an ac4C-dependent manner

Cited by 54 publications

References 43 publications

Identification and Functional Analysis of Lysine 2-Hydroxyisobutyrylation in Cyanobacteria

Identification and Functional Analysis of Lysine 2-Hydroxyisobutyrylation in Cyanobacteria

Antibody-Free Fluorine-Assisted Metabolic Sequencing of RNA N4-Acetylcytidine

Targeting N4‐acetylcytidine suppresses hepatocellular carcinoma progression by repressing eEF2‐mediated HMGB2 mRNA translation

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Antibody-Free Fluorine-Assisted Metabolic Sequencing of RNA N⁴-Acetylcytidine