RNA N4-acetylcytidine modification in human cancers: from molecular function to oncogenic mechanisms

TL;DR

This review explores how the RNA modification ac4C, catalyzed by NAT10, contributes to cancer progression and treatment resistance, offering potential for new therapies.

Contribution

The paper provides a comprehensive synthesis of how the NAT10-ac4C axis drives oncogenic processes and its therapeutic implications.

Findings

NAT10-catalyzed ac4C stabilizes mRNAs encoding oncoproteins, promoting cancer progression.

The ac4C modification influences cancer hallmarks like proliferation, metastasis, and therapy resistance.

NAT10 inhibitors show promise in resensitizing tumors to conventional treatments in preclinical models.

Abstract

The RNA epitranscriptome represents a critical layer of gene regulation, with N4-acetylcytidine (ac4C) emerging as a pivotal modification in cancer biology. Catalyzed exclusively by N-acetyltransferase 10 (NAT10), ac4C decorates a broad spectrum of RNAs, profoundly influencing their stability and translation efficiency. This review synthesizes recent advances illuminating how the NAT10-ac4C axis drives oncogenic processes, including sustained proliferation, metabolic reprogramming, invasion and metastasis, immunosuppression, and therapy resistance by selectively stabilizing mRNAs encoding key oncoproteins. We detail the molecular mechanisms underpinning these roles across diverse malignancies, highlighting context-dependent functions and intricate cross-talk with other signal pathways. Furthermore, we explore the translational promise of this pathway, discussing NAT10 inhibitors and rational combination therapies that resensitize tumors to conventional treatments in preclinical models. Unraveling the full regulatory circuitry of ac4C will not only deepen our understanding of cancer pathogenesis but also pave the way for novel diagnostic and therapeutic strategies in precision oncology.

Biochemistry; Epigenetics; Cancer

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