How HPV rewires sugar chemistry in cervical cancer cells

Cervical cancer remains one of the most common malignancies affecting women worldwide, with an estimated 662,301 new cases and 348,874 deaths recorded globally in 2022 according to GLOBOCAN data. Persistent infection with high-risk human papillomavirus is the principal initiating event in the disease, and sustained expression of the viral E6 and E7 oncoproteins drives malignant transformation and tumor maintenance. Yet viral positivity alone cannot explain why some lesions progress to invasive cancer while others do not, or why established tumors develop resistance to treatment. A new review published in Frontiers in Molecular Biosciences examines whether a chemical modification of proteins, known as O-GlcNAcylation, could connect the metabolic demands imposed by HPV oncogenes to the way cervical cancer cells manage energy production and stress.

O-GlcNAcylation is the reversible attachment of a single N-acetylglucosamine sugar to serine or threonine residues on proteins inside the cell. The enzyme O-GlcNAc transferase, or OGT, adds this modification, while O-GlcNAcase, or OGA, removes it. The donor substrate for the reaction, UDP-GlcNAc, is manufactured by the hexosamine biosynthetic pathway from inputs drawn from glucose, glutamine, lipids, and nucleotides. Because the pathway integrates these multiple nutrient streams, O-GlcNAc cycling can report on nutrient availability, biosynthetic demand, and cellular stress without acting as the sole upstream controller of those states. Unlike classical glycosylation in the secretory pathway, this modification occurs on proteins in the nucleus, cytosol, and mitochondrial matrix, and it can respond rapidly to nutrients, oxidative stress, viral infection, and therapeutic pressure.

The review, authored by Yingying Zhang, Yimei Tao, Huirong He, Ping Li, and Minbin Chen, grades the available evidence according to experimental model, temporal context, and causal depth. The authors distinguish between observations made in untreated cervical cancer models, acute responses to treatment, and durable resistance, arguing that these represent distinct biological situations that should not be interpreted interchangeably. Their central conclusion is sobering: cervical cancer studies support links between O-GlcNAcylation and pathways involved in growth and survival, but no mitochondrial O-GlcNAcylation site has been causally validated in HPV-positive cervical cancer. Mechanisms inferred from cardiac, lung, colorectal, and other experimental systems remain hypotheses requiring validation in HPV-positive cervical cancer cells, patient-derived models, and clinical samples.

Sustained E6 and E7 expression increases metabolic demand in cervical cancer cells through several established routes. E6 promotes degradation of the p53 tumor suppressor mainly through an E6AP-dependent mechanism, while E7 binds pRB family proteins through its LXCXE motif and releases G1/S checkpoint control. The oncoproteins also engage c-Myc, HIF-1α, PI3K/Akt, PKM2, and E2F-related programs that regulate glycolysis, glutamine utilization, nucleotide synthesis, and adaptation to oxidative stress. Notably, HPV E6 can elevate OGT expression and O-GlcNAcylation, and E6/E7-associated proliferation is accompanied by increased glycolysis and biosynthetic demand. Greater glycolytic activity can alter the availability of hexosamine pathway substrates, but the review stresses that current evidence does not demonstrate that O-GlcNAcylation initiates metabolic reprogramming. The authors position changes in the hexosamine pathway, OGT, and OGA as a potentially responsive and feedback-regulated layer that requires direct flux, substrate, and rescue experiments in HPV-positive models.

HPV genotype adds another layer of complexity. HPV16 and HPV18, the predominant oncogenic genotypes in cervical cancer, produce E6 and E7 proteins that differ in sequence, expression control, splice products, and affinity for selected host partners. A common comparison between SiHa cells, which are HPV16-positive squamous carcinoma cells, and HeLa cells, which are HPV18-positive adenocarcinoma cells, confounds viral genotype with histology, integration pattern, viral copy number, and host genomic background. Within the literature surveyed, the authors identified no comparison of matched HPV16 and HPV18 models that quantified hexosamine pathway flux, UDP-GlcNAc abundance, OGT or OGA activity, or site-specific O-GlcNAcylation. An available metabolomic comparison showed features of Warburg metabolism in both cell lines but different nicotinamide and redox profiles: SiHa cells accumulated NAD, NADH, and several glutathione pathway metabolites, whereas HeLa cells showed increased nicotinamide riboside and cysteine. Because the two lines are not isogenic, these differences cannot be assigned to HPV genotype alone.

Several cervical cancer findings do reach a higher standard of evidence. Under the review’s classification, two reported relationships meet the Tier 1A criteria, which require a functionally validated O-GlcNAcylation site in a cervical cancer model. Site-directed mutation of NF-κB p65 at Thr322 or Thr352 in HeLa cells reduced CXCR4 expression, and stable OGT depletion reduced lung metastasis in a mouse model. In CaSki cells, which are HPV16-positive, OGT overexpression and depletion, STAT1 knockout, and mutation of Ser727 supported a role for tumor-cell STAT1 O-GlcNAcylation in macrophage polarization and phagocytosis in coculture. However, the study did not examine O-GlcNAcylation within macrophages themselves, and independent replication, in vivo validation, and confirmation in patient-derived samples remain necessary. Other cervical cancer work, including studies linking OGT to E6/E7 promoter activity through host cell factor 1, to epithelial-mesenchymal transition, to PTEN stability through GFPT1, and to cisplatin sensitivity, provides functional evidence without a validated causal modification site and is classified as Tier 1B.

The mitochondrial question sits at the heart of the review. Cervical cancer models show variable mitochondrial oxidative activity rather than a consistent reduction in oxidative phosphorylation. In HeLa and SiHa cells and cervical tumor tissues, formation of a mitochondrial complex containing CKS2 and SSBP1 was associated with an OXPHOS-related transcriptional program and chemoradioresistance. Mitochondria therefore remain active contributors to ATP production, ROS signaling, biosynthetic precursor supply, apoptosis control, and stress responses in these tumors. Among all studies included in the review, only one directly manipulated intramitochondrial O-GlcNAcylation: an acute 30-minute intervention in isolated cardiac mitochondria reported changes in Complex I activity, respiratory capacity, and ROS release. Without independent replication or validation in cervical cancer, the authors treat this as preliminary evidence from another model rather than an established mechanism.

Candidate mitochondrial substrates identified in other systems illustrate the evidence gap. Drp1, a key mediator of mitochondrial fission, has been shown to be O-GlcNAcylated in non-cervical models, where the modification is associated with mitochondrial recruitment and increased fission, but direct Drp1 O-GlcNAcylation and its functional consequences have not been established in HPV-positive cervical cancer. OPA1, essential for inner-membrane fusion and cristae stability, has been associated with mitochondrial phenotypes involving O-GlcNAcylation in other systems, but current evidence is insufficient to establish it as a direct O-GlcNAcylation substrate. In non-small cell lung cancer, O-GlcNAcylation of HK2 regulated HK2 activity, mitochondrial dynamics, proliferation, and apoptosis, and O-GlcNAcylation of PFK1 altered glucose partitioning with potential effects on antioxidant capacity through the pentose phosphate pathway. These findings identify testable indirect routes by which O-GlcNAcylation could influence mitochondrial redox balance through glucose partitioning without directly modifying mitochondrial proteins, but their relevance to HPV-positive cervical cancer remains untested.

Temporal context matters for interpreting treatment-related findings. In HeLa cells, DNA damage acutely recruited OGT to damage sites, and stress-induced increases in O-GlcNAcylation can be transient in other experimental systems. Stable OGT depletion increased cisplatin sensitivity after 24 hours in HeLa cells, and metformin treatment for 24 hours was associated with reduced AMPK O-GlcNAcylation, cell cycle arrest, and apoptosis. Because OGT depletion had been established before cisplatin treatment, the experiment did not test whether cisplatin induced a protective O-GlcNAcylation response. Neither study used a validated resistant model, so the results are described as responses at 24 hours rather than evidence of acquired resistance. The review specifies that acquired resistance in cell models requires repeated drug selection from a sensitive parental line, confirmation that the selected cells are less sensitive than the parental line, and testing of whether resistance persists after drug withdrawal.

The authors conclude that current evidence supports individual components of a proposed framework linking E6/E7-associated metabolic demand, hexosamine pathway activity, and substrate-specific O-GlcNAcylation to mitochondrial and immune adaptation, but not the complete causal sequence in HPV-positive cervical cancer. Direct cervical cancer evidence is strongest for selected non-mitochondrial substrates and signaling effects. The principal gap is the absence of site-specific validation of candidate mitochondrial proteins in HPV-positive cervical cancer, together with direct measurements of respiration, ROS, membrane potential, and mitochondrial dynamics. Translational applications, including biomarkers based on O-GlcNAcylation in tissue, blood, cervicovaginal fluid, or extracellular vesicles, and selective combination strategies targeting defined substrates, remain early preclinical or conceptual. Any future intervention must also be evaluated in normal cervical epithelial and immune cells to establish tumor selectivity and exclude impairment of antitumor immunity. O-GlcNAcylation, the review concludes, is best positioned as a context-dependent regulatory layer within a broader network of post-translational modifications rather than as the sole initiator of metabolic reprogramming.

Subject of Research: O-GlcNAcylation as a proposed link between HPV E6/E7 metabolic demand and mitochondrial remodeling in cervical cancer

Article Title: HPV E6/E7, O-GlcNAcylation and mitochondrial remodeling in cervical cancer: mechanistic links and translational opportunities

Article References: Zhang, Y., Tao, Y., He, H., Li, P., & Chen, M. (2026). HPV E6/E7, O-GlcNAcylation and mitochondrial remodeling in cervical cancer: mechanistic links and translational opportunities. Frontiers in Molecular Biosciences, 13, Article 1919738. https://doi.org/10.3389/fmolb.2026.1919738

Image Credits: AI Generated

DOI: 10.3389/fmolb.2026.1919738

Keywords: cervical cancer, HPV E6/E7, O-GlcNAcylation, hexosamine biosynthetic pathway, mitochondrial metabolism, OGT, OGA, treatment resistance, tumor microenvironment, metabolic reprogramming, post-translational modification, evidence hierarchy