Helicobacter pylori-induced NAT10 stabilizes MDM2 mRNA via RNA acetylation to facilitate gastric cancer progression

Abstract

Background N4-acetylcytidine (ac4C), a widespread modification in human mRNAs that is catalyzed by the N-acetyltransferase 10 (NAT10) enzyme, plays an important role in promoting mRNA stability and translation. However, the biological functions and regulatory mechanisms of NAT10-mediated ac4C were poorly defined. Methods ac4C mRNA modification status and NAT10 expression levels were analyzed in gastric cancer (GC) samples and compared with the corresponding normal tissues. The biological role of NAT10-mediated ac4C and its upstream and downstream regulatory mechanisms were determined in vitro and in vivo. The therapeutic potential of targeting NAT10 in GC was further explored. Results Here, we demonstrated that both ac4C mRNA modification and its acetyltransferase NAT10 were increased in GC, and increased NAT10 expression was associated with disease progression and poor patient prognosis. Functionally, we found that NAT10 promoted cellular G2/M phase progression, proliferation and tumorigenicity of GC in an ac4C-depedent manner. Mechanistic analyses demonstrated that NAT10 mediated ac4C acetylation of MDM2 transcript and subsequently stabilized MDM2 mRNA, leading to its upregulation and p53 downregulation and thereby facilitating gastric carcinogenesis. In addition, Helicobacter pylori (Hp) infection contributed to NAT10 induction, causing MDM2 overexpression and subsequent p53 degradation. Further investigations revealed that targeting NAT10 with Remodelin showed anti-cancer activity in GC and augmented the anti-tumor activity of MDM2 inhibitors in p53 wild-type GC. Conclusions These results suggest the critical role of NAT10-mediated ac4C modification in GC oncogenesis and reveal a previously unrecognized signaling cascade involving the Hp-NAT10-MDM2-p53 axis during GC development.

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

“…Notably, when cells were cultured with an inhibitor of NAT10, Remodelin (10 μM), 10,38,39 which has been applied to inhibit ac 4 C modification in vitro and vivo, 40,41 the Remodelin not only inhibited NAT10 but also increased sensitivity to cisplatin in bladder cancer and mouse xenografts. 41 As shown in Figure 3B, after cell treatment with the addition of Remodelin for 24 h, the Fac 4 C modification on RNA was notably weakened.…”

Molecular Basis for RNA Cytidine Acetylation by NAT10

“…Although it is an essential protein, data indicates NAT10 may be a viable therapeutic target for the treatment of various cancers and cellular aging, and has been implicated in the regulation of p53 17,[29][30][31][32][33][34][35] , as well as the human accelerated aging genetic disorder, Hutchinson-Gilford Progeria Syndrome (HGPS) 36,37 . Heterozygous knockout of NAT10 has been demonstrated to modulate HGPS phenotypes in a mouse model 38 .…”

Recent advances in the potential role of RNA N4-acetylcytidine in cancer progression

“…Deng et al [ 78 ] studied the relationship between ac4C modification and GC occurrence and found that NAT10 is significantly up-regulated in GC cells versus healthy cells. H. pylori infection contributes to NAT10 induction, regulating p53 stability via MDM2 proto-oncogene (MDM2).…”