O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis.

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• High-risk human papillomaviruses (HPVs) cause various cancers, but the mechanisms driving neoplasia progression are unclear.
• O-linked GlcNAcylation (O-GlcNAc) is a dynamic post-translational modification implicated in cellular processes.

Purpose of the Study:

• To investigate the role of O-GlcNAc and its associated enzymes in HPV-mediated cancer development.
• To elucidate the molecular mechanisms linking HPV oncoproteins to cellular transformation and oncogenesis.

Main Methods:

• Assessed O-GlcNAc, O-GlcNAc transferase (OGT), and O-GlcNAcase (OGA) levels in HPV-associated cervical neoplasms.
• Utilized HPV oncogene transduction (E6/E7) in cell models (MEFs, HeLa, TC-1) to study O-GlcNAc pathway alterations.
• Employed chemical inhibitors and genetic knockdown (OGT) to evaluate the impact on cellular phenotypes, c-MYC stability, and tumorigenesis.

Main Results:

• O-GlcNAc and OGT levels were significantly elevated in HPV-positive cervical neoplasms.
• HPV oncogenes increased OGT, O-GlcNAc levels, promoted cell proliferation, and reduced senescence.
• O-GlcNAc inhibition impaired transformed phenotypes; HPV E6 increased c-MYC stability via O-GlcNAcylation.
• OGT knockdown or O-GlcNAc inhibition suppressed c-MYC, tumorigenesis, and metastasis in HPV-transformed cells.

Conclusions:

• Aberrant O-GlcNAcylation, driven by OGT, is a key mechanism in HPV oncoprotein-mediated cellular transformation.
• Targeting the O-GlcNAc pathway, particularly OGT, presents a potential therapeutic strategy for HPV-associated malignancies.