Multiomics analysis of the effects of NAT10 deletion on genome organization and transcription

NAT10 is the only known RNA acetyltransferase responsible for N4-acetylcytidine (ac4C) modification of RNA. However, the detailed mechanism by which NAT10 contributes to cancer and metastasis remains unclear. Loss of NAT10 acetylation activity significantly reduces lung metastasis in both allograft and genetically engineered mouse models of breast cancer. Furthermore, NAT10-mediated ac4C-modified tRNAs associate with chromatin associated factors such as p300/CBP. Loss of NAT10 and ac4C-modified tRNAs disrupts p300/CBP function, alters genome-wide histone acetylation, reorganizes enhancers, and changes the expression of genes critical for metastasis, including chemokines that recruit metastasis-promoting myeloid cells to the tumor microenvironment. These findings highlight a distinct role for NAT10 in regulating enhancer activity in metastatic tumor cells and reveal its impact on tumor-immune interactions that contribute to metastatic progression.