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NSD2 is upregulated by high-risk HPV E6/E7 and modulates epithelial differentiation in HPV-associated Head and Neck Cancer

ABSTRACT: Epigenetic alterations are a key hallmark of cancer and are increasingly recognized as promising clinical biomarkers and therapeutic targets. In recent years Head and Neck Squamous Cell Carcinomas (HNSCC) have been classified into two subtypes: HPV-positive (HPV+), driven by human papillomavirus (HPV) infections, and the HPV-negative (HPV-), associated with environmental risk factors. Although exhibiting distinct molecular and clinicopathological features, both subtypes lack effective, tailored therapies. Thus, profiling their epigenetic landscape could thus have important clinical implications. In this study, we employed a quantitative mass spectrometry approach to profile histone post-translational modification (hPTMs) in HPV+ and HPV- HNSCC. We found that the histone mark H3K36me2 is significantly enriched in the HPV+ subtype and that this alteration is driven by hr-HPV E6/E7 oncoproteins which also upregulate NSD2, a histone methyltransferase specific for H3K36 dimethylation. Both H3K36me2 and NSD2 are upregulated in several cancers. Given the NSD2’s context and cell-type-dependent functions, we investigated its role in HPV+ and HPV- HNSCC. We observed that NSD2 regulates cell proliferation and migration in both the subtypes. Importantly, we identified a novel role for NSD2 in regulating epithelial cell differentiation, particularly in HPV+ HNSCC, where it appears to modulate the E6/E7-induced differentiation blockade. Overall, our findings highlight H3K36me2 as a potential biomarker for patient stratification and position NSD2 as a promising therapeutic target across HNSCC subtypes, regulating both shared and subtype-specific oncogenic pathways. Specifically, NSD2 inhibition in HPV+ tumors may restore epithelial differentiation and arrest tumor progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313615 | GEO | 2026/02/11

REPOSITORIES: GEO

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Project description:Introduction: Human Papilloma Virus (HPV) is associated with a subset of head and neck squamous cell carcinoma (HNSCC), between 15% and 35% of HNSCC harboring HPV, almost exclusively of subtype 16. Demographic and exposure differences between HPV-positive (+) and negative (-) HNSCCs suggest that HPV(+) tumors may constitute a subclass with different biology, while clinical differences have also been observed. In this study, gene expression profiles of HPV(+) and (-) tumors were compared to further explore the biological effect of HPV in HNSCC. Methods: Thirty-six HNSCC tumors were analyzed for gene expression using Affymetrix Human 133U Plus 2.0 GeneChip and for HPV using consensus primers for HPV L1, E6 and E7 by PCR and RT-PCR. Results: Eight (22%) of 36 tumors were positive for HPV, all of the HPV 16 subtype, and the HPV positive samples also expressed viral HPV E6 mRNA determined by RT-PCR. Patients with HPV(+) HNSCCs were on average younger than those with HPV(-) tumors (mean age 50.2 vs. 58.7). Statistical analysis using Significance Analysis of Microarrays (SAM) based on HPV status as a supervising parameter resulted in a list of 91 genes that were differentially expressed with statistical significance. Results for a sub-set of these genes were verified by RT-PCR. Genes highly expressed in HPV(+) samples included cell cycle regulators (p16INK4A, p18 and CDK2) and transcription factors (TAF7L, RFC4, RPA2 and TFDP2). The microarray data were also investigated using DIGMap to map genes by chromosomal location. A large number of genes on chromosome 3q24-qter was found to be overrepresented in HPV(+) tumors. Conclusion: The gene expression profile associated with HPV reflects alterations in cell cycle and proliferation signals. Further investigation of differentially expressed genes may reveal the unique pathways in HPV(+) tumors that may explain the different natural history and biological properties of these tumors. These properties may be exploited as a target of novel therapeutic agents in HNSCC treatment. Keywords: HPV, HNSCC, head and neck cancer, human, human papilloma virus

Project description:Head and neck cancer (HNC) is the fifth most common malignancy worldwide with an annual mortality rate of 200,000. About 90% of HNC can be classified as head and neck squamous cell carcinomas (HNSCC), of which approximately 75% are attributed to alcohol and tobacco consumption and 25 are associated with human papillomavirus (HPV), predominantly HPV16. HPV-associated OPC have better prognosis and a more favorable response to therapy as compared to HPV-negative tumors. Viral oncoproteins are capable of transforming primary human keratinocytes from either genital or oral epithelia in vitro and most likely play the same role in vivo, by disrupting cell-cycle regulatory pathways leading to a genetic progression to ano-genital cancer and OPC. However, the precise mechanisms by which HPV mediates malignant transformation of keratinocytes in the upper digestive tract epithelia are not entirely clear. HPV E7-mediated inactivation of pRb results in overexpression of p16INK4A, which is commonly used as a clinical surrogate marker for HPV positivity/activity. However, high p16INK4A alone has insufficient sensitivity and specificity as a biomarker of HPV positivity in different mucosal sub-sites of HNC. Therefore, increasing emphasis is being placed on the assessment of viral load and E7 oncogene expression, resulting in further classification of HPV positive OPC as HPV-active and HPV-inactive. Differences in risk factors, age of presentation, clinical behavior and gene expression profiles indicate that HPV-positive and HPV-negative tumors develop via different molecular mechanisms and are biologically distinct. This study aimed to compare the gene expression profiles of HPV-negative and HPV-inactive OPCs from both African American and European American patients, and determine their biological and racial differences. ANALYSIS 4: Four-condition, one-color experiment: African American (AA) HPV-inactive, African American (AA) HPV-negative, European American (EA) HPV-inactive, European American (EA) HPV-negative oropharyngeal tumor samples. Biological replicates: 4 AA HPV Inactive samples, 8 AA HPV Negative samples, 4 EA HPV Inactive samples and 8 EA HPV Negative samples,

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NSD2 is upregulated by high-risk HPV E6/E7 and modulates epithelial differentiation in HPV-associated Head and Neck Cancer

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