Epigenetic reprogramming of cell fate decisions in oral squamous cell carcinoma: Crosstalk between survival signaling, genome surveillance and tumor plasticity (Review)

Oral squamous cell carcinoma (OSCC) remains associated with substantial morbidity, resistance to treatment and recurrence.Genetic alterations and epigenetic regulation jointly influence tumor behavior.DNA methylation, histone modifications, chromatin remodeling and non-coding RNAs provide a framework for examining proliferation, apoptosis, DNA-damage responses and cellular plasticity.The present review distinguishes OSCC-specific clinical observations and functional experiments from mechanisms established in other types of cancer and hypotheses requiring direct validation.Tissue methylation analyses identify alterations at selected tumor-suppressor and repair-related loci, while experiments involving arecoline-associated regulation of the ANK1/miR-486-3p axis and HOTAIR-associated chromatin regulation illustrate more specific mechanistic associations.These findings do not establish the coordinated suppression of repair and apoptosis across OSCC.The proposed repair-survival trade-off, termed a 'pseudo-repair' phenotype herein, is therefore treated as a hypothesis rather than a validated molecular subtype.Its evaluation requires paired epigenetic and expression measurements, pathway-specific repair assays, apoptosis measurements, and perturbation and rescue experiments.Phenotypic heterogeneity should also be distinguished from mutation burden and chromosomal instability, which require direct genomic measurements.Epigenetic therapies and tissue or liquid-biopsy markers remain critical research directions; however, evidence from other types of cancer cannot establish their clinical utility in OSCC.Linking locus-specific regulation to functional outcomes in well-characterized oral models and independently validated patient cohorts will help identify reproducible mechanisms and prioritize translational studies.Contents 1. Introduction 2. Cell fate decisions and epigenetic regulation 3. Epigenetic mechanisms and interpretation of evidence 4. Epigenetic regulation of survival signaling and apoptotic checkpoints 5. Environmental and cellular inputs to epigenetic regulation 6. Epigenetic alterations at selected tumor-suppressor loci 7. Epigenetic crosstalk and proposed pathway coordination 8. Genome surveillance and the proposed repair-survival trade-off 9. Phenotypic plasticity and candidate biomarkers 10.Investigational epigenetic therapies 11.Research priorities for epigenetic systems oncology 12.