FOXA1,　a　transcription　factor　involved　in　epigenetic　reprogramming,　is　crucial　for　breast　cancer　progression.　However,　the　mechanisms　by　which　FOXA1　achieves　its　oncogenic　functions　remain　elusive.　Here,　we　demonstrate　that　the　O-linked　beta-N-acetylglucosamine　modification　(O-GlcNAcylation)　of　FOXA1　promotes　breast　cancer　metastasis　by　orchestrating　the　transcription　of　numerous　metastasis　regulators.　O-GlcNAcylation　at　Thr(432),　Ser(441),　and　Ser(443)　regulates　the　stability　of　FOXA1　and　promotes　its　assembly　with　chromatin.　O-GlcNAcylation　shapes　the　FOXA1　interactome,　especially　triggering　the　recruitment　of　the　transcriptional　repressor　methyl-CpG　binding　protein　2　and　consequently　stimulating　FOXA1　chromatin-binding　sites　to　switch　to　chromatin　loci　of　adhesion-related　genes,　including　EPB41L3　and　COL9A2.　Site-specific　depletion　of　O-GlcNAcylation　on　FOXA1　affects　the　expression　of　various　downstream　genes　and　thus　inhibits　breast　cancer　proliferation　and　metastasis　both　in　vitro　and　in　vivo.　Our　data　establish　the　importance　of　aberrant　FOXA1　O-GlcNAcylation　in　breast　cancer　progression　and　indicate　that　targeting　O-GlcNAcylation　is　a　therapeutic　strategy　for　metastatic　breast　cancer.