MYB-driven NAT10-IGF2BP3 RNA modification axis sustains MAPK signaling and promotes adenoid cystic carcinoma progression.

The oncogenic transcription factor MYB is a genomic hallmark of adenoid cystic carcinoma (ACC), yet its downstream effectors and the underlying epitranscriptomic mechanisms remain incompletely understood. In this study, we combined bioinformatic analysis of clinical samples with mechanistic experiments in ACC cell lines and xenograft models, employing ChIP-qPCR, dual-luciferase reporter assays, acRIP-seq, meRIP-qPCR, RNA stability assays, and functional rescue experiments to investigate whether MYB drives ACC progression by orchestrating a functional crosstalk between key RNA modifications. We identified that MYB directly binds to the promoter of NAT10, the sole writer for N4-acetylcytidine (ac4C), and transcriptionally upregulates its expression. Subsequently, NAT10 installs ac4C modification on IGF2BP3 mRNA, enhancing its stability and increasing its expression, while IGF2BP3 in turn stabilizes NAT10 mRNA in an m6A-dependent manner, thereby forming a MYB-initiated, self-reinforcing circuit. Disruption of this circuit, either by knocking down NAT10/IGF2BP3 or by pharmacologically inhibiting NAT10 with Remodelin, attenuated the activation of the MAPK signaling pathway and suppressed ACC cell proliferation, migration, and invasion; importantly, Remodelin treatment significantly inhibited tumor growth in vivo. Collectively, our study unveils a novel oncogenic pathway in which MYB instigates a NAT10-IGF2BP3 RNA modification reciprocal regulatory circuit to promote ACC progression, highlighting the MYB-NAT10-IGF2BP3 axis as a promising therapeutic target for ACC.