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N4-acetylcytidine-dependent GLMP mRNA stabilization by NAT10 promotes head and neck squamous cell carcinoma metastasis and remodels tumor microenvironment through MAPK/ERK signaling pathway

ABSTRACT: N4-acetylcytidine (ac4C) is a posttransciptional RNA modification regulating in various important bioprocess. However, the role in human cancer, especially lymph node metastasis, remains largely unknown. Here, we showed NAT10, as the only “writer” of ac4C mRNA modification, was highly expressed in HNSCC patients with lymph node metastasis. High NAT10 levels in lymph node of HNSCC patients predicted poor overall survival. Moreover, we found the high expression of NAT10 was positively upregulated by NRF1 transcription factor. Gain and loss-of-function displayed that NAT10 promoted cell metastasis in mice. Mechanistically, NAT10 induced ac4C modification of GLMP and stabilized its mRNA, which triggered the activation of MAPK/ERK signaling pathway. Lastly, the NAT10’s specific inhibitor Remodelin could inhibit HNSCC tumorigenesis via 4-NQO-induced murine tumor model and remodel the tumor microenvironment, including angiogenesis, CD8+ T cell and Treg recruitment. These results demonstrated that NAT10 promoted lymph node metastasis of HNSCC via ac4C-dependent stabilization of GLMP transcript, providing a potential epitranscriptomic-targeted therapeutic strategy for HNSCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239900 | GEO | 2023/08/08

REPOSITORIES: GEO

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Project description:Generation of the "epitranscriptome through post-transcriptional ribonucleoside modification embeds a layer of regulatory complexity into RNA structure and function. Here we describe N4-acetylcytidine (ac4C) as an mRNA modification that is catalyzed by the acetyltransferase NAT10. Transcriptome-wide mapping of ac4C revealed discretely acetylated regions that were enriched within coding sequences. Ablation of NAT10 reduced ac4C detection at the mapped mRNA sites and was globally associated with target mRNA down-regulation. Analysis of mRNA half-lives revealed a NAT10-dependent increase in stability in the cohort of acetylated mRNAs. mRNA acetylation was further demonstrated to enhance substrate translation in vitro and in vivo. Codon content analysis within ac4C peaks uncovered a biased representation of cytidine within wobble sites that was empirically determined to influence mRNA decoding efficiency. These findings expand the repertoire of mRNA modifications to include an acetylated residue and establish a role for ac4C in the regulation of mRNA translation. Generation of the “epitranscriptome” through post-transcriptional ribonucleoside modification embeds a layer of regulatory complexity into RNA structure and function. Here we describe N4-acetylcytidine (ac4C) as a novel mRNA modification that is catalyzed by the acetyltransferase NAT10. Transcriptome-wide mapping of ac4C revealed discretely acetylated regions that were distributed across target mRNAs with the majority of peaks occurring within coding regions. Depletion of ac4C through NAT10 ablation revealed a relationship to gene expression wherein loss of ac4C was globally associated with transcript downregulation. The presence of ac4C within coding sequences was associated with elevated ribosome density and enhanced translation, as assessed in vivo and in vitro. In addition to expanding the repertoire of mRNA modifications to include an acetylated residue, these findings highlight a role for ac4C in the control of mRNA metabolism at the level of translation.

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N4-acetylcytidine-dependent GLMP mRNA stabilization by NAT10 promotes head and neck squamous cell carcinoma metastasis and remodels tumor microenvironment through MAPK/ERK signaling pathway

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