Abstract
Background: While chronic oxidative stress is an established driver of carcinogenesis, the mechanisms by which transient molecular insults are converted into stable, heritable pro-malignant states are a key area of investigation. Epigenetic modifications provide a plausible link between environmental or metabolic stressors and the long-term alterations in gene expression that precede overt cancer.
Objective: This review explores how chronic oxidative stress, often initiated by latent micronutrient deficiencies, orchestrates a durable epigenetic reprogramming that silences tumor-suppressor genes and activates oncogenic pathways. It details the transition from a reversible stress response to a fixed "epigenetic lock-in" that defines the premalignant state.
Findings: The manuscript details how persistent reactive oxygen species (ROS) disrupt the function of critical epigenetic-modifying enzymes, including iron-dependent TET and JmjC demethylases. This impairment leads to aberrant DNA hypermethylation at CpG islands and the deposition of repressive histone marks (e.g., H3K27me3), which silence key tumor-suppressor genes. Concurrently, non-coding RNAs (ncRNAs) guide these repressive complexes, reinforcing a malignant gene expression program that can be passed through cell divisions. This epigenetic memory explains the long latency periods observed in premalignant lesions and establishes a molecular foundation for field cancerization.
Conclusion: Epigenetic alterations function as the central mechanism translating chronic metabolic stress into a durable, cancer-prone cellular identity. These modifications are not only biomarkers for early risk assessment but also represent a crucial, druggable checkpoint. Therapeutic strategies targeting epigenetic regulators, such as DNMT, HDAC, and BET inhibitors, offer a promising avenue to reset the aberrant epigenetic landscape, thereby preventing or reversing malignant progression.