O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis

Significance O-linked GlcNAcylation is a reversible posttranslational protein modification on serine or threonine residues and regulates multiple cellular signaling pathways. We discovered elevated O-GlcNAc and O-GlcNAc transferase (OGT) in HPV-associated cervical neoplasms relative to the normal cervix. We show that HPVE6 upregulates OGT, increases O-GlcNAc, stabilizes c-MYC via O-GlcNAc, and enhances HPV oncogene activities. Conversely, suppression of O-GlcNAc in HPV-transformed cells by knocking down or inhibiting OGT impairs HPV oncogene-induced activities and impedes tumor growth in animal models. Thus, O-GlcNAc plays a critical role in HPV-induced carcinogenesis, and targeting O-GlcNAc might prove to be a potential therapeutic approach.