FOXA1 O-GlcNAcylation-mediated transcriptional switch governs metastasis capacity in breast cancer

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.

Automated summary

Based on the study of FOXA1 O-beta-N-acetylglucosamine modification (O-GlcNAcylation), it was found that O-GlcNAcylation promotes breast cancer metastasis by regulating the transcription of multiple metastasis regulators. O-GlcNAcylation regulates the stability of FOXA1 and promotes its chromatin assembly, shaping the interactome of FOXA1 and triggering the recruitment of transcriptional repressor methyl-CpG binding protein 2. Site-specific depletion of O-GlcNAcylation on FOXA1 affects the expression of various downstream genes, inhibiting breast cancer proliferation and metastasis. These findings establish the importance of aberrant FOXA1 O-GlcNAcylation in breast cancer progression and suggest that targeting O-GlcNAcylation could be a therapeutic strategy for metastatic breast cancer.