Integrated Multiomics Analysis Suggests Statin-Associated Perturbation of DNA Repair Signaling in Colorectal Cancer Cells

Statins are widely prescribed lipid-lowering agents that also exert pleiotropic anticancer effects, such as induction of apoptosis and ferroptosis, modulation of autophagy, and remodeling of the tumor microenvironment. Consistent with these multifaceted actions, statins have demonstrated synergistic activity with several chemotherapeutic agents. Emerging evidence indicates that statins modulate the activity of key DNA damage response kinases, such as ataxia-telangiectasia (ATM) and checkpoint kinase 2 (CHK2), in colorectal cancer cells, suggesting a potential impact on DNA repair pathways. To investigate this possibility, publicly available transcriptomic, proteomic, and phosphoproteomic datasets derived from colorectal cancer models treated with atorvastatin or lovastatin were systematically analyzed. Genes and proteins associated with DNA repair exhibiting differential expression, as well as proteins with altered phosphorylation status, were identified. These datasets were subsequently subjected to pathway enrichment and protein-protein interaction network analyses to determine whether statin exposure preferentially affected specific DNA repair pathways. Integrated multi-omics analysis revealed coordinated perturbation of tumor protein p53 (TP53)-centered DNA repair signaling, including pathways involved in TP53 regulation and double-strand break repair. Taken together, these findings suggest that statin-induced alteration of TP53-mediated DNA repair signaling may promote the persistence of DNA damage, thereby increasing the sensitivity of tumor cells to chemotherapy and potentially mitigating resistance mechanisms in colorectal cancer.