NatD epigenetically activates FOXA2 expression to promote breast cancer progression by facilitating MMP14 expression

N-α-acetyltransferase D (NatD) mediates N-α-terminal acetylation of histone H4 (Nt-Ac-H4), but its role in breast cancer metastasis remains unknown. Here, we show that depletion of NatD directly represses the expression of FOXA2, and is accompanied by a significant reduction in Nt-Ac-H4 enrichment at the FOXA2 promoter. We show that NatD is commonly upregulated in primary breast cancer tissues, where its expression level correlates with FOXA2 expression, enhanced invasiveness, and poor clinical outcomes. Furthermore, we show that FOXA2 promotes the migration and invasion of breast cancer cells by activating MMP14 expression. MMP14 is also upregulated in breast cancer tissues, where its expression level correlates with FOXA2 expression and poor clinical prognosis. Our study shows that the NatD-FOXA2-MMP14 axis functions as a key signaling pathway to promote the migratory and invasive capabilities of breast cancer cells, suggesting that NatD is a critical epigenetic modulator of cell invasion during breast cancer progression. [Display omitted] •Upregulation of NatD is associated with poor prognosis in breast cancer patients•NatD promotes breast cancer cell migration and invasion in vitro and in vivo•NatD catalyzes the Nt-Ac-H4 of the FOXA2 promoter and promotes its expression•FOXA2 binds to the promoter of MMP14 and promotes its expression Natural sciences; Biological sciences; Systems biology; Cancer systems biology; Cancer