Prognostic and Immunological Role of mRNA ac4C Regulator NAT10 in Pan-Cancer: New Territory for Cancer Research?

Yang, Chuanxi; Wu, Tingting; Zhang, Jing; Liu, Jinhui; Zhao, Kun; Sun, Wei; Zhou, Xin; Kong, Xiangqing; Shi, Jing

doi:10.3389/fonc.2021.630417

Cited by 29 publications

(29 citation statements)

References 39 publications

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“…NAT10 also participates in modifying different types of RNA in the nucleolus, including the splicing of precursor rRNA at positions A0, A1 and A2 in yeast 22 . According to the most recent report, the high expression of the mRNA ac4C writer NAT10 indicates poorer prognosis of various malignancies and NAT10‐mediated ac4C modification on mRNA promotes gastric cancer metastasis and EMT 25 . Although NAT10‐mediated modification of ac4C peaks on RNA and proteins has been elucidated, knowledge about the role of ac4C on mRNA and its regulatory networks in cancer remains intricate to this day.…”

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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“…More than 100 epigenetic modifications of mRNA, including N6-adenosine methylation (m6A), cytosine hydroxylation (m5C), and N1-adenosine methylation (m1A), have been revealed in mediating the stability, function, and splicing process of targeted mRNAs (9)(10)(11). Previous studies on m6A have reported that two important readers, YTHDF2 and YTHDC1, were respectively located in the nucleus and cytoplasm of oocytes, which played crucial roles in mRNA degradation, transcriptome switching, and selective splicing during oocyte maturation.…”

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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“…This proposal could also be extrapolated to other cancers showing significant correlation with THUMPD1 expression. Distinct from the results of pan-cancer analysis of NAT10, our proposition demonstrates the difference between NAT10 and THUMPD1 in clinical and immunological function, though they both serve as the writing tools of ac4C [ 34 ]. Hence, further studies are required to determine the detailed difference and the possible underlying mechanism.…”

Section: Discussionmentioning

confidence: 97%

“…Here, with distinct prognosis in high THUMPD1 expression cohorts, KIRC and LIHC were treated as the representation to support the idea that THUMPD1 may play distinct roles in different cancer types. According to pan-cancer analysis of NAT10, the partner of THUMPD1 for mRNA acetylation, high NAT10 expression is associated with worse survival in LIHC, lymphoma and colorectal cancer [ 34 ]. Although NAT10 and THUMPD1 work synergistically, their effects on prognosis of diverse cancer types are not totally the same.…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer analysis of N4-acetylcytidine adaptor THUMPD1 as a predictor for prognosis and immunotherapy

Liu

Yang

et al. 2021

Bioscience Reports

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Background: THUMPD1 is a specific RNA adaptor that assists acetylation of mRNA and production of N4-acetylcytidine (ac4C). However, it remains unclear whether THUMPD1 plays a part in tumorigenesis and therapeutic efficacy. Here, we analyzed the expression profiles and prognostic value of THUMPD1 in pan-cancer and gained insights into the correlation between THUMPD1 expression level and immunotherapy efficacy. Methods: Gene expression pattern and its correlation with prognosis, immune cell infiltration in pan-cancer were obtained from GTEx, CCLE and TCGA databases, with Kaplan-Meier method and Spearman correlation analysis used. Western blotting and immunofluorescence on clinical samples was performed to validate our database-derived results. Correlation between THUMPD1 expression level and immunotherapy responses was also explored, based on clinical cohorts receiving PD-L1 antibody therapy. Finally, GSEA was performed to show the possible tumorigenic mechanism. Results: THUMPD1 was highly expressed in most cancer types, and this elevated expression indicated poor or improved prognosis for different cancers. In kidney renal clear cell carcinoma (KIRC) and rectum adenocarcinoma (READ), patients with higher THUMPD1 expression exhibited a better prognosis, while liver hepatocellular carcinoma (LIHC) patients had worse prognosis. Besides, THUMPD1 was significantly associated with immune cell infiltration, tumor mutation burden (TMB), microsatellite instability (MSI)，immune checkpoints and neoantigen in many cancer types. Further, more clinical advantages and therapeutic responses were observed in patients with high THUMPD1 expression. Conclusions: THUMPD1 may serve as a novel predictor to evaluate cancer prognosis and immune therapy efficacy in diverse cancer types.

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Prognostic and Immunological Role of mRNA ac4C Regulator NAT10 in Pan-Cancer: New Territory for Cancer Research?

Cited by 29 publications

References 39 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

Pan-cancer analysis of N4-acetylcytidine adaptor THUMPD1 as a predictor for prognosis and immunotherapy

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