EZH2 reads DNA 6mA to regulate survival and drug resistance of human head and neck squamous carcinoma by suppressing RIOX2-CDKN1A-NRF2 signaling axis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE212452 | GEO | 2025/08/18
REPOSITORIES: GEO
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Project description:We performed short hairpin RNA (shRNA)-mediated knockdown (KD) experiments to abrogate ALKBH1 expression. To comprehensively understand the underlying mechanism of ALKBH1 in HNSCC, we performed RNA-seq assay and profiled gene expression alteration of HNSCC cells upon ALKBH1 knockdown.
2025-08-18 | GSE212451 | GEO
Project description:we attempted to comprehensively assess whether EZH2 recognizes 6mA modification at the global level. We first performed chromatin immunoprecipitation following sequencing (ChIP-seq) in human HNSCCs using antibody that recognize EZH2 to determine its genome-wide occupancies.We further investigated 6mA profiling using methylated DNA immunoprecipitation following sequencing (MeDIP-seq).
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Project description:To determine whether 6mA has a role in guiding EZH2 recruitment, we focused on ALKBH1, the well-defined DNA 6mA demethylase in mammals, and knocked down ALKBH1 expression in HNSCC cells using shRNAs. We performed MeDIP-seq and ChIP-seq using these cells, and found that ALKBH1 deletion led to an obvious gain of 6mA peaks, which accompanied with enrichment of EZH2 and H3K27me3.
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Project description:BackgroundPeople with head and neck cancer have higher comorbidity levels but it remains unclear if pretreatment comorbidity is an independent prognosticator in head and neck cancer.MethodsSurvival analyses were performed using data from participants in a UK multicentre cohort study with cancers of the oral cavity (n = 668), oropharynx (n = 1074), and larynx (n = 530). Survival analyses were incrementally adjusted for age, sex, marital status, income, education, stage, alcohol, and smoking.ResultsAfter adjusting for demographic, clinical, and behavioral confounders, higher baseline comorbidity was associated with reduced overall survival (mild comorbidity HR = 1.4, 95% CI = 1.1, 1.7; moderate comorbidity HR = 1.7, 95% CI = 1.3, 2.2; severe comorbidity HR = 2.8, 95% CI = 1.9, 4.; P-trend<.001).ConclusionsOur findings suggest that comorbidity is an independent prognosticator for overall survival in head and neck cancer. Comorbid illnesses should be considered in the assessment and treatment planning of people with head and neck cancer.
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Project description:BackgroundThe association between diet and head and neck cancer (HNC) survival is unclear.MethodsCox proportional hazard models measured the association between fruit, vegetable, and deep-fried food intake and HNC overall survival adjusting for clinical, social and lifestyle variables including smoking, alcohol, and HPV status.ResultsFruit and vegetable intake and improved survival were associated in minimally adjusted analyses. Following adjustment for smoking and alcohol consumption (fully adjusted analyses), the association with survival disappeared for fruit (HR 0.91, 95% CI 0.67, 1.23; P for trend = .55) and attenuated for vegetables (HR 0.79, 95% CI 0.61, 1.03; P for trend = .04). We observed no association between survival and deep-fried food intake in minimally adjusted or fully adjusted analyses (HR 0.88 95% CI 0.72, 1.07; P for trend = .13).ConclusionsVegetable intake and HNC survival are modestly associated. There is some confounding by tobacco and alcohol consumption.
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Project description:Enhancer of Zeste homologue 2 (EZH2) overexpression is associated with tumor proliferation, metastasis, and poor prognosis. Targeting and inhibition of EZH2 is a potentially effective therapeutic strategy for head and neck squamous cell carcinoma (HNSCC). We analyzed EZH2 mRNA expression in a well-characterized dataset of 230 (110 original and 120 validation cohorts) human head and neck cancer samples. This study aimed to investigate the effects of inhibiting EZH2, either via RNA interference or via pharmacotherapy, on HNSCC growth. EZH2 upregulation was significantly correlated with recurrence (p < 0.001) and the methylation index of tumor suppressor genes (p < 0.05). DNMT3A was significantly upregulated upon EZH2 upregulation (p = 0.043). Univariate analysis revealed that EZH2 upregulation was associated with poor disease-free survival (log-rank test, p < 0.001). In multivariate analysis, EZH2 upregulation was evaluated as a significant independent prognostic factor of disease-free survival (hazard ratio: 2.085, 95% confidence interval: 1.390⁻3.127; p < 0.001). Cells treated with RNA interference and DZNep, an EZH2 inhibitor, showed the most dramatic changes in expression, accompanied with a reduction in the growth and survival of FaDu cells. These findings suggest that EZH2 upregulation is correlated with tumor aggressiveness and adverse patient outcomes in HNSCC. Evaluation of EZH2 expression might help predict the prognosis of HNSCC patients.
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Project description:BackgroundFor patients with head and neck squamous cell carcinoma (HNSCC), failure of definitive radiation combined with cisplatin nearly universally results in death. Although hyperactivation of the Nrf2 pathway can drive radiation and cisplatin resistance along with suppressed anti-tumor immunity, treatment-refractory HNSCC tumors may retain sensitivity to targeted agents secondary to synergistic lethality with other oncogenic drivers (e.g., NOTCH1 mutations).PurposeWe evaluated the efficacy of PI3K inhibitors (PI3Ki) in bypassing Nrf2-mediated cisplatin resistance in HNSCC.MethodsWe measured transcriptomic, metabolomic and signaling changes driven by PI3Kis in cisplatin-resistant HNSCCs in vitro and tested efficacy in vivo in subcutaneous, orthotopic and metastatic xenograft models using immunodeficient and humanized murine models of HNSCC coupled with spatial transcriptomics.ResultsThe PI3K pathway is activated in Nrf2-driven cisplatin-resistant HNSCC and is suitable for blockade as demonstrated in an in vivo shRNA screen. The PI3Ki gedatolisib inhibits cisplatin-resistant HNSCC proliferation, induces G2M arrest and potentiates cisplatin effectiveness through activation of autophagy, senescence and disruption of fatty acid metabolism. Gedatolisib suppresses HNSCC tumor growth in orthotopic and metastatic settings and demonstrates profound anti-tumor activity in humanized murine models of HNSCC, coupled with a reduction in hypoxia-rich regions and reduced infiltration by regulatory T lymphocytes.ConclusionOur findings emphasize the critical role of the PI3K-AKT-mTOR pathway in cisplatin-resistant HNSCC and highlight the therapeutic potential of PI3K inhibitors. Gedatolisib induced metabolic regulation and substantial re-sensitization of resistant cells to cisplatin, positioning it as a promising candidate for combination therapies aimed at overcoming primary chemo-radiation failure in HNSCC.
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Project description:BackgroundWe propose a novel prognostic biomarker-based strategy for increasing the efficacy of radiotherapy (RT) in head and neck squamous cell carcinoma (HNSCC).Materials and methodsWe identified genes associated with superoxide dismutase 2 (SOD2) and nuclear factor erythroid-2-related factor 2 (NRF2) from gene-expression data of The Cancer Genome Atlas (TCGA) by calculating Pearson correlation. Patients were divided into two groups using hierarchical clustering. Colony-formation assay was performed to determine radioresistance in HNSCC cell line CAL27. Pathway analysis was conducted using The Database for Annotation, Visualization and Integrated Discovery (DAVID).ResultsWe developed a 49-gene signature with SOD2- and NRF2-associated genes. Using mRNA expression data for the 49-gene signature, we performed hierarchical clustering to stratify patients into two subtypes, subtype A and B. In the TCGA cohort, subgroup A demonstrated a better prognosis than subgroup B in patients who received RT. The signature robustness was evaluated in other independent cohorts. We showed through colony-formation assay that depletion of SOD2 or NRF2 leads to increased radiosensitivity.ConclusionWe identified and validated a robust gene signature of SOD2- and NRF2-associated genes in HNSCC and confirmed their link to radioresistance using in vitro assay, providing a novel biomarker for the evaluation of HNSCC prognosis.
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Project description:Head and neck cancer (HNC) is the seventh most common cancer worldwide, with a 5-year overall survival of 50-60%. Despite known survival factors, unexpected deaths underscore the need to refine pre-treatment survival predictions. This study aimed to identify novel data-driven HNC patient phenotypes, associated features and predict overall survival using deep survival clustering model VaDeSC. We used a retrospective cohort of 1341 HNC patients from Helsinki University Hospital, utilizing their pre-treatment clinical and demographic data from electronic health records. We identified six previously unrecognized HNC phenotypes with distinct survival patterns, highlighting the significance of BMI, sleep apnoea, TNM stage, tumour site, treatment intention, gender, and age-related treatment modalities. VaDeSC demonstrated strong predictive accuracy, clustering performance and generalizability, achieving C-index of 0.895 ± 0.015 on training and 0.782 ± 0.013 on test data. The phenotype purity was 0.102 ± 0.11 on training-validation data and 0.143 ± 0.006 on test data. Our findings demonstrated that clustering pre-treatment clinical survival data offers intuitively interpretable results with accurate individualised predictions. This approach holds significant potential for novel phenotype discovery across various diseases and endpoints.
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Project description:BackgroundThe COVID-19 pandemic has required triage and delays in surgical care throughout the world. The impact of these surgical delays on survival for patients with head and neck squamous cell carcinoma (HNSCC) remains unknown.MethodsA retrospective cohort study of 37 730 patients in the National Cancer Database with HNSCC who underwent primary surgical management from 2004 to 2016 was performed. Uni- and multivariate analyses were used to identify predictors of overall survival. Bootstrapping methods were used to identify optimal time-to-surgery (TTS) thresholds at which overall survival differences were greatest. Cox proportional hazard models with or without restricted cubic splines were used to determine the association between TTS and survival.ResultsThe study identified TTS as an independent predictor of overall survival (OS). Bootstrapping the data to dichotomize the cohort identified the largest rise in hazard ratio (HR) at day 67, which was used as the optimal TTS cut-point in survival analysis. The patients who underwent surgical treatment longer than 67 days after diagnosis had a significantly increased risk of death (HR, 1.189; 95% confidence interval [CI], 1.122-1.261; P < 0.0001). For every 30-day delay in TTS, the hazard of death increased by 4.6%. Subsite analysis showed that the oropharynx subsite was most affected by surgical delays, followed by the oral cavity.ConclusionsIncreasing TTS is an independent predictor of survival for patients with HNSCC and should be performed within 67 days after diagnosis to achieve optimal survival outcomes.
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