O-GlcNAcylation on serine 40 of histone H2A promotes proliferation and invasion in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is characterized by resistance to conventional treatment and a poor prognosis. The O-linked β-N-acetylglucosamine (O-GlcNAc) modification of proteins has been reported to affect cancer progression. However, the key O-GlcNAc proteins involved in TNBC phenotypes remain unclear. Our previous study demonstrated that serine 40 of histone H2A was modified by O-GlcNAcylation (H2AS40Gc). Since S40 is located inside the globular domain of H2A, H2AS40Gc may be involved in the regulation of gene expression by altering chromatin conformation and could serve as the molecular basis for TNBC. The present study showed that H2AS40Gc levels were significantly higher in TNBC than in the other breast cancer subtypes. Using TNBC cells in which H2AS40Gc levels were depleted, we found that H2AS40Gc is required to promote cell proliferation and migration. The underlying mechanism of this promotion involves the accumulation of H2AS40Gc in the promoter region of KDM5B, a demethylase for lysine 4 of histone H3 (H3K4) that represses the expression of KDM5B, resulting in increased H3K4 trimethylation and elevated expression of genes related to proliferation and migration. Our findings clearly indicate that H2AS40Gc functions to promote proliferation and migration through KDM5B suppression and provide new insights into potential therapeutic approaches for TNBC.