Abstract
Introduction: Epigenetic dysregulation is increasingly recognized as a fundamental driver of cell cycle checkpoint failure in colorectal cancer. Beyond genetic mutations, epigenetic mechanisms provide a dynamic and potentially reversible layer of control over cyclin-dependent kinase activity and tumor progression. This mechanistic critical review examines how epigenetic alterations reshape cell cycle regulation in colorectal cancer and evaluates their translational relevance.
Methods: This review adopts a critical mechanistic approach, integrating and interpreting evidence from experimental, translational and clinical studies addressing epigenetic regulation of cell cycle control in colorectal cancer. Rather than following a systematic review framework, the literature was evaluated conceptually to identify dominant mechanisms, areas of convergence and unresolved controversies.
Results: Evidence indicates that aberrant DNA methylation, histone modifications and chromatin remodeling converge to repress key cyclin-dependent kinase inhibitors including p16INK4a, p21Cip1 and p27Kip1. These epigenetic alterations sustain cyclin–CDK activity thereby promote bypass of G1/S checkpoint control and facilitate uncontrolled proliferation. Importantly, epigenetic heterogeneity across colorectal tumors contributes to variable therapeutic responses and resistance to both conventional and epigenetic-targeted therapies.
Conclusion: Epigenetic control of cell cycle checkpoints represents a central and therapeutically exploitable mechanism in colorectal cancer. A mechanistic understanding of these regulatory networks highlights opportunities for rational combination strategies and precision-based interventions while underscoring current knowledge gaps that warrant further investigation.