NAT10 promotes cancer metastasis by modulating p300/CBP activity through chromatin-associated tRNA [ChIP-seq]

Acetylation of proteins and RNA is crucial for development and cancer progression. NAT10 is the sole RNA acetylase responsible for N4-acetylcytidine (ac4C) modification of various RNAs. Our study reveals that NAT10 loss significantly reduces lung metastasis in breast cancer mouse models. NAT10 interacts with a mechanosensitive, metastasis-susceptibility protein complex at the nuclear pore. Mechanistically, NAT10-mediated acetylation of chromatin-associated tRNAs enhances p300/CBP activity. Without NAT10, acetylation of these tRNAs decreases, leading to p300/CBP inactivation and mislocalization. As a result, NAT10 depletion disrupts enhancer organization, altering gene transcription critical for metastasis, including reduced chemokines that recruit myeloid cells and create a less metastasis-prone tumor microenvironment. Our findings highlight the distinct role of NAT10 in acetylated tRNA-dependent regulation of enhancer function in metastatic tumor cells and its impact on tumor-immune interactions influencing metastasis. Overall design: We performed ChIP-seq of H3K27ac, H4K20ac, and H3K27me3 in WT and Nat10 knockout (KO-c43) 4T1 mouse mammary tumor cells. In addition, we also performed ChIP-seq of Nat10, Pan Brd4, V5-tagged Brd4-short isoform, endogenous RRP1B, HA-tagged Rrp1b and Sipa1 in parental 4T1 cells.