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

Abstract

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.

N‐acetyltransferase 10 promotes colon cancer progression by inhibiting ferroptosis through N4‐acetylation and stabilization of ferroptosis suppressor protein 1 (FSP1) mRNA

“…Studies have also shown that ac4C acetylation, an mRNA modification, regulated telomerase activity, RNA synthesis, DNA damage repair, and mRNA stability [12,43]. It is also associated with the development, progression, and prognosis of various human diseases, especially cancer [19,44,45]. Given that it is the only acetyltransferase that catalyzes the ac4C modification, NAT10 is significantly associated with the prognosis of a variety of malignant correlation with NAT10 expression in colon cancer tumor tissues from the GEO dataset (GSE31782) were analyzed.…”

NAT10: An RNA cytidine transferase regulates fatty acid metabolism in cancer cells

“…10 In bladder cancer, NAT10-mediated reduction of ac4C modification was reported to suppress the stability and translational efficiency of BCL9L, SOX4 and AKT1, thereby inhibiting cancer progression. 11 Although many information point to the impact of NAT10-dependent ac4C modification on different cancer mechanisms, knowledge of the impact of NAT10 in pathways is still obscure. Recently, we reported the effect of Remodelin, the only known small molecule inhibitor of NAT10 on mitochondrial lipid metabolism 12 .…”

“…In bladder cancer, NAT10‐mediated reduction of ac4C modification was reported to suppress the stability and translational efficiency of BCL9L, SOX4 and AKT1, thereby inhibiting cancer progression 11 …”

Translational Regulation by eIFs and RNA Modifications in Cancer

“…The downregulation of NAT10 was shown to result in the reduced ac 4 C modification of mRNA in specific regions of bladder cancer cells, impairing the translational stability and efficiency of BCL9L, SOX4, and AKT1. The deletion of NAT10 was also shown to reduce tumor burden in bladder cancer xenograft and transgenic mouse models [ 253 ]. Another study found that ac 4 C was elevated in the urine of CRC patients and was positively correlated with Duke’s CRC stage but significantly decreased after the radical resection of CRC [ 254 ].…”