NAT10 promotes gastric cancer metastasis via N4-acetylated COL5A1

Zhang, Yigan; Jing, Yuan-Xue; Wang, Yin-Xue; Tang, Jianming; Zhu, Xiaoran; Jin, Wei‐Lin; Wang, Yiqing; Wang, Yuan; Li, Xiangkai; Li, Xun

doi:10.1038/s41392-021-00489-4

Cited by 82 publications

(79 citation statements)

References 4 publications

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“…5 The level of m 6 A, m 7 G or ac4C modifications in mRNA-specific motifs is variable depending on protein-binding, resulting in changes to mRNA stability and translation efficiency. [6][7][8][9][10][11] These modifications are responsible for tumour proliferation, metastasis, maintenance of stemness and cellfate decisions. 10,[12][13][14] Previous studies demonstrate that METTL3, an N6-methyltransferase that methylates adenosine residues at the N6 position of some RNAs, is involved in the m 6 A modification of ITGA6 and the AFF4/NF-κB/MYC pathway.…”

Section: Introductionmentioning

confidence: 99%

NAT10‐mediated mRNA N4‐acetylcytidine modification promotes bladder cancer progression

Wang

Zhang

et al. 2022

Clinical & Translational Med

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Background Dysregulation of the epitranscriptome causes abnormal expression of oncogenes in the tumorigenic process. Previous studies have shown that NAT10 can regulate mRNA translation efficiency through RNA acetylation. However, the role of NAT10‐mediated acetylation modification in bladder cancer remains elusive. Methods The clinical value of NAT10 was estimated according to NAT10 expression pattern based on TCGA data set and the tumor tissue array. Acetylated RNA immunoprecipitation sequencing was utilized to explore the role of NAT10 in mRNA ac4C modification. Translation efficiency and mRNA stability assay were applied to study the effect of NAT10‐deletion on target genes. The nude mouse model and genetically engineered mice were conducted to further verify the characteristics of NAT10 in promoting BLCA progression and regulating downstream targets. Results NAT10 was essential for the proliferation, migration, invasion, survival and the stem‐cell‐like properties of bladder cancer cell lines. NAT10 was responsible for mRNA ac4C modification in BLCA cells, including BCL9L, SOX4 and AKT1. Deficient NAT10 in both xenograft and transgenic mouse models of bladder cancer reduced the tumor burden. Furthermore, acetylated RNA immunoprecipitation sequencing data and RNA immunoprecipitation qPCR results revealed that NAT10 is responsible for a set of ac4C mRNA modifications in bladder cancer cells. Inhibition of NAT10 led to a loss of ac4C peaks in these transcripts and represses the mRNA's stability and protein expression. Mechanistically, the ac4C reduction modification in specific regions of mRNAs resulting from NAT10 downregulation impaired the translation efficiency of BCL9L, SOX4 and AKT1 as well as the stability of BCL9L, SOX4. Conclusions In summary, these findings provide new insights into the dynamic characteristics of mRNA's post‐transcriptional modification via NAT10‐dependent acetylation and predict a role for NAT10 as a therapeutic target in bladder cancer. Highlights NAT10 is highly expressed in BLCA patients and its abnormal level predicts bladder cancer progression and low overall survival rate. NAT10 is necessary and sufficient for BLCA tumourigenic properties. NAT10 is responsible for ac4C modification of target transcripts, including BCL9L, SOX4 and AKT1. NAT10 may serve as an effective and novel therapeutic target for BLCA.

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Section: Introductionmentioning

confidence: 99%

NAT10‐mediated mRNA N4‐acetylcytidine modification promotes bladder cancer progression

Wang

Zhang

et al. 2022

Clinical & Translational Med

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“…NAT10, as the only identified acetyltransferase, is thought to play critical roles in promoting mRNA stability and maintaining translation fidelity through ac4C modification on the specific sequence of target mRNAs (16). The dysregulation of NAT10 inhibited cell development progress and led to various diseases, such as gastric cancer and systemic lupus erythematosus (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

NAT10 Maintains OGA mRNA Stability Through ac4C Modification in Regulating Oocyte Maturation

et al. 2022

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In vitro maturation (IVM) refers to the process of developing immature oocytes into the mature in vitro under the microenvironment analogous to follicle fluid. It is an important technique for patients with polycystic ovary syndrome and, especially, those young patients with the need of fertility preservation. However, as the mechanisms of oocyte maturation have not been fully understood yet, the cultivation efficiency of IVM is not satisfactory. It was confirmed in our previous study that oocyte maturation was impaired after N-acetyltransferase 10 (NAT10) knockdown (KD). In the present study, we further explored the transcriptome alteration of NAT10-depleted oocytes and found that O-GlcNAcase(OGA) was an important target gene for NAT10-mediated ac4C modification in oocyte maturation. NAT10 might regulate OGA stability and expression by suppressing its degradation. To find out whether the influence of NAT10-mediated ac4C on oocyte maturation was mediated by OGA, we further explored the role of OGA in IVM. After knocking down OGA of oocytes, oocyte maturation was inhibited. In addition, as oocytes matured, OGA expression increased and, conversely, O-linked N-acetylglucosamine (O-GlcNAc) level decreased. On the basis of NAT10 KD transcriptome and OGA KD transcriptome data, NAT10-mediated ac4C modification of OGA might play a role through G protein–coupled receptors, molecular transduction, nucleosome DNA binding, and other mechanisms in oocyte maturation. Rsph6a, Gm7788, Gm41780, Trpc7, Gm29036, and Gm47144 were potential downstream genes. In conclusion, NAT10 maintained the stability of OGA transcript by ac4C modification on it, thus positively regulating IVM. Moreover, our study revealed the regulation mechanisms of oocytes maturation and provided reference for improving IVM outcomes. At the same time, the interaction between mRNA ac4C modification and protein O-GlcNAc modification was found for the first time, which enriched the regulation network of oocyte maturation.

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“…Interestingly, ac4C modification is known to exist within mRNAs, but the results of NAT10 RIP-seq revealed that NAT10binding sequences were enriched not only in exons but also in introns (Figure 3A). Results of NAT10 RIP-seq in another study (Zhang et al, 2021) also showed a peak within the intronic sequence of COL5A1 mRNA, and ac4C promoted the stability but not translation efficiency of COL5A1. Based on these results, it is established that NAT10 binds to intronic sequences, but it is not known whether NAT10 binding results in ac4C production in intronic regions of pre-mRNAs.…”

Section: Discussionmentioning

confidence: 90%

NAT10-Mediated N4-Acetylcytidine of RNA Contributes to Post-transcriptional Regulation of Mouse Oocyte Maturation in vitro

Xiang

Zhou

Guo

et al. 2021

Front. Cell Dev. Biol.

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N4-acetylcytidine (ac4C), a newly identified epigenetic modification within mRNA, has been characterized as a crucial regulator of mRNA stability and translation efficiency. However, the role of ac4C during oocyte maturation, the process mainly controlled via post-transcriptional mechanisms, has not been explored. N-acetyltransferase 10 (NAT10) is the only known enzyme responsible for ac4C production in mammals and ac4C-binding proteins have not been reported yet. In this study, we have documented decreasing trends of both ac4C and NAT10 expression from immature to mature mouse oocytes. With NAT10 knockdown mediated by small interfering RNA (siRNA) in germinal vesicle (GV)-stage oocytes, ac4C modification was reduced and meiotic maturation in vitro was significantly retarded. Specifically, the rate of first polar body extrusion was significantly decreased with NAT10 knockdown (34.6%) compared to control oocytes without transfection (74.6%) and oocytes transfected with negative control siRNA (72.6%) (p < 0.001), while rates of germinal vesicle breakdown (GVBD) were not significantly different (p = 0.6531). RNA immunoprecipitation and high-throughput sequencing using HEK293T cells revealed that the modulated genes were enriched in biological processes associated with nucleosome assembly, chromatin silencing, chromatin modification and cytoskeletal anchoring. In addition, we identified TBL3 as a potential ac4C-binding protein by a bioinformatics algorithm and RNA pulldown with HEK293T cells, which may mediate downstream cellular activities. Taken together, our results suggest that NAT10-mediated ac4C modification is an important regulatory factor during oocyte maturation in vitro and TBL3 is a potential ac4C-binding protein.

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NAT10 promotes gastric cancer metastasis via N4-acetylated COL5A1

Cited by 82 publications

References 4 publications

NAT10‐mediated mRNA N4‐acetylcytidine modification promotes bladder cancer progression

NAT10‐mediated mRNA N4‐acetylcytidine modification promotes bladder cancer progression

NAT10 Maintains OGA mRNA Stability Through ac4C Modification in Regulating Oocyte Maturation

NAT10-Mediated N4-Acetylcytidine of RNA Contributes to Post-transcriptional Regulation of Mouse Oocyte Maturation in vitro

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