The role and mechanism of NAT10-mediated ac4C modification in tumor development and progression

Abstract

RNA modification has emerged as a crucial area of research in epigenetics, significantly influencing tumor biology by regulating RNA metabolism. N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification, the sole known acetylation in eukaryotic RNA, influences cancer pathogenesis and progression. NAT10 is the only writer of ac4C and catalyzes acetyl transfer on targeted RNA, and ac4C helps to improve the stability and translational efficiency of ac4C-modified RNA. NAT10 is highly expressed and associated with poor prognosis in pan-cancers. Based on its molecular mechanism and biological functions, ac4C is a central factor in tumorigenesis, tumor progression, drug resistance, and tumor immune escape. Despite the increasing focus on ac4C, the specific regulatory mechanisms of ac4C in cancer remain elusive. The present review thoroughly analyzes the current knowledge on NAT10-mediated ac4C modification in cancer, highlighting its broad regulatory influence on targeted gene expression and tumor biology. This review also summarizes the limitations and perspectives of current research on NAT10 and ac4C in cancer, to identify new therapeutic targets and advance cancer treatment strategies.

Keywords: N4‐acetylation (ac4C); N‐acetyltransferase 10 (NAT10); RNA modification; cancer; epitranscriptome.

FIGURE 1

Distribution of ac4C on RNAs. The modification of ac4C occurs on different types of RNAs, including mRNA, tRNA, rRNA, snoRNA, miRNA, lncRNA, and circRNA,. Indicated ac4C modifications are labeled at the corresponding modification sites. ac4C, N4‐acetylcytosine; CDSs, coding sequences; UTR, untranslated regions; snoRNA, small nucleolar RNA; pri‐miRNA primary microRNA, pre‐miRNA precursor microRNA.

FIGURE 2

Mechanism and function of ac4C regulated by NAT10 on mRNAs. Mechanism and function of ac4C regulated by NAT10 on mRNAs. Chemical structures of ac4C modifications. ac4C modification can be installed on mRNA, enhances its stability, and thus avoids its fate of degradation. NAT10, N‐acetyltransferase 10; ac4C, N4‐acetylcytosine; CDSs, coding sequences; UTR, untranslated regions.

FIGURE 3

NAT10 plays a critical role in cancer. ac4C plays a positive role in regulating the progression of various cancers as illustrated. In bladder cancer, NAT10 is activated by NF‐κB signaling, promotes the expression of BCL9L, SOX4, AKT1 through ac4C to inhibit apoptosis of cancer cells. It also mediated DNA damage repair and chemotherapy resistance through ac4C modification of AHNAK and p21. In breast cancer, NAT10 promoted tumor chemoresistance by regulating the activation of EMT and ac4C modification of MDR1 and BCRP. Radiotherapy‐ and chemotherapy‐mediated DNA damage activates the ac4C modification of MORC2 to regulate the cell cycle, enhancing treatment resistance. In cervical cancer, NAT10 is transcriptionally activated by HOXC8, and it regulates the expression of GLUT4 and KHK by enhancing the ac4C modification of FOXP1, thus promoting tumor lactate production and the development of immunosuppressive microenvironment. In addition, NAT10 can be suppressed by circMAST1, affecting the stability of the critical transcription factor YAP1. In colorectal cancer, upregulation of NAT10 promotes ac4C modification of FSP1 to facilitate ferroptosis resistance and stimulates WNT/β‐catenin pathway via KIF23. In various tumors, NAT10 mediates tumor progression, metastasis, therapy resistance, and the formation of immunosuppressive microenvironment by promoting ac4C activation of downstream oncogenic pathways. Khib, lysine 2‐hydroxyisobutyrylation; MITF, microphthalmia‐associated transcription factor; EMT, epithelial–mesenchymal transition; ER stress, endoplasmic reticulum stress; MDSC, myeloid‐derived suppressor cell; ANKZF1, ankyrin repeat and zinc finger peptidyl TRNA hydrolase 1; YWHAE, tyrosine 3‐monooxygenase/tryptophan 5‐monooxygenase; FSP1, ferroptosis suppressor protein 1; KIF23, kinesin family member 23; NOTCH3, Notch receptor 3; MDM2, the murine double minute 2; SEPT9, septin 9; AXL, AXL receptor tyrosine kinase; FNTB, the farnesyltransferase subunit beta gene; YTHDC1, YTH N6‐methYLADENOSINE RNA BINDING PROTEIN C1; m6A, N(6)‐methyladenosine; CEBPB, CCAAT enhancer binding protein beta; FOXM1, Forkhead box M1; TFAP2A, transcription factor AP‐2 alpha; HNRNPUL1, heterogeneous nuclear ribonucleoprotein U like 1; FOXP1, Forkhead box P1; GLUT4, glucose transporter 4; KHK, ketohexokinase; MORC2, MORC family CW‐type zinc finger 2; MDR1, breast cancer resistance protein 1; BCRP, breast cancer resistance protein; BCL9L, B‐cell lymphoma 9‐like.

FIGURE 4

Overview of the ac4C‐related signaling pathway in cancer. In cancer cells, activation of the NF‐κB signaling pathway promotes NAT10 expression. Activated p65 binds to the NAT10 promoter and regulates its expression in a transcriptional manner. NAT10, inhibited by Remodelin, mediates mRNA ac4C modification and promotes the downstream protein expression thereby activating the Wnt/β‐catenin pathway. NAT10 boosts c‐Myc upregulation, regulates cell cycle and EMT through activation of the Wnt/β‐catenin pathway, ultimately promoting tumor progression. NF‐κB, nuclear factor kappa‐B; TCF/LEF, T‐cell factor/lymphoid enhancer‐binding factor. TLR, Toll‐like receptor; EMT, epithelial–mesenchymal transition.

FIGURE 5

Limitations and challenges in current research of ac4C. (A) Lack of identification of reader and eraser: ac4C is a dynamic process that requires writer, eraser, and reader to regulate the ac4C modification status and function of target genes. Current studies have only identified the one and only writer NAT10, with a lack of reader and eraser studies. (B) Lack of targeted inhibitors. Targeted inhibitors for ac4C writer, eraser, and reader are required to be explored for clinical cancer therapy. (C) Lack of detection methods. Currently, the detection of ac4C relies on liquid mass spectrometry and acRIP. (D) Lack of biomarkers for diagnosis and prognosis. ac4C remains to further validate for use as a cancer biomarker. ac4C, N4‐acetylcytosine.