Elina Chen

Background: Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide and develops through the accumulation of genetic and epigenetic alterations in colonic epithelial cells.¹ Although aspirin has long been recognized for its chemo preventive effects against CRC, the molecular mechanisms underlying these benefits extend beyond traditional cyclooxygenase (COX) inhibition.^1,4 Emerging evidence suggests that aspirin functions as an epigenetic regulator capable of modifying DNA methylation, histone acetylation, and histone methylation to suppress malignant transformation and tumor progression.^1,4 Aspirin may also target colorectal cancer stem-like cells (CSCs), a therapy-resistant population linked to recurrence and metastasis. Additionally, recent studies demonstrate that aspirin may selectively benefit patients with specific genomic alterations involving the phosphoinositide 3-kinase (PI3K) pathway.⁵ Understanding these epigenetic and genomic interactions may help identify specific target populations that might benefit more from Aspirin treatment and further refine CRC prevention and treatment strategies.

Objective: This focused literature review examines the epigenetic mechanisms by which aspirin and NSAIDs contribute to colorectal cancer prevention and therapy, with particular focus on CSC regulation through p300-mediated histone acetylation, alongside DNA methylation, histone methylation, cancer stem-like cell (CSC) regulation, and genomic predictors of aspirin responsiveness.

Search Methods: A literature search was conducted using the PubMed database for studies published after 2018. Search terms included “colorectal cancer,” “aspirin,” “NSAIDs,” “epigenetics,” “DNA methylation,” “histone acetylation,” and “cancer stem cells.” Primary experimental studies, translational investigations, and randomized clinical trials relevant to aspirin-mediated epigenetic regulation in CRC were evaluated.

Results: Longitudinal studies of healthy colonic mucosa from patients who underwent colonoscopy demonstrated that long-term aspirin use was associated with reduced age-related hypermethylation and preservation of a younger epigenetic profile compared with nonusers.¹ Aspirin users also exhibited lower mitotic epigenetic clock scores, suggesting decreased stem cell division rates and reduced accumulation of replication-associated mutations linked to tumorigenesis.² Beyond methylation, mechanistic studies show that aspirin can directly target colorectal CSCs through chromatin remodeling. Aspirin enhances p300-mediated histone H3K9 acetylation at the Fas ligand (FasL) promoter, increasing FasL-mediated apoptosis in CSC populations while sparing normal epithelial cells.³ In addition to promoting cell death, aspirin may further dismantle CSC programs by altering repressive histone marks. Aspirin reduced expression of histone demethylases KDM6A and KDM6B, increasing histone methylation at promoters of inflammation-associated stemness genes such as ICAM3.⁴ This suppressed CSC self-renewal and tumor progression through a COX-independent mechanism involving inhibition of the ICAM3/Src/PI3K signaling pathway.⁴ Translating these mechanistic insights into human outcomes, a randomized placebo-controlled trial evaluated low-dose aspirin in patients with surgically resected CRC harboring PI3K pathway alterations.⁵ The study demonstrated that aspirin significantly reduced recurrence rates in this cohort, with the therapeutic benefit being particularly pronounced in patients with PIK3CA hotspot mutations in exons 9 and 20.⁵

Conclusions: Current evidence supports aspirin as a multifaceted epigenetic regulator in CRC prevention and treatment. Aspirin appears to suppress epigenetic aging, reduce mitotic activity, and importantly target CSC survival through p300-driven histone acetylation and FasL-mediated apoptosis, while also repressing stemness-associated signaling through histone methylation.^1-4 These findings expand the understanding of aspirin’s anti-cancer effects beyond COX inhibition and highlight its role in modulating the colonic epigenome. The observed benefit in PI3K-altered tumors further emphasizes the importance of integrating tumor genomics into personalized oncology therapy.⁵ Future studies investigating epigenetic biomarkers and aspirin responsiveness may improve risk stratification and optimize individualized CRC prevention and adjuvant treatment strategies.

Works Cited

1. Noreen F, Chaber-Ciopinska A, Regula J, et al. Longitudinal analysis of healthy colon establishes aspirin as a suppressor of cancer-related epigenetic aging. Clin Epigenetics. 2020;12(1):164.
2. Nwanaji-Enwerem JC, Nze C, Cardenas A, et al. Long-term Aspirin Use and Epigenetic Mitotic Clocks for Cancer Risk Prediction: Findings in Healthy Colon Mucosa and Recommendations for Future Epigenetic Aging Studies. Epigenetics Commun. 2021;1(1):5.
3. Chen Z, Li W, Qiu F, et al. Aspirin cooperates with p300 to activate the acetylation of H3K9 and promote FasL-mediated apoptosis of cancer stem-like cells in colorectal cancer. Theranostics. 2018;8(16):4447-4461.
4. Zhang X, Du R, Luo N, et al. Aspirin mediates histone methylation that inhibits inflammation-related stemness gene expression to diminish cancer stemness via COX-independent manner. Stem Cell Res Ther. 2020;11(1):370.
5. Martling A, Hed Myrberg I, Nilbert M, et al. Low-Dose Aspirin for PI3K-Altered Localized Colorectal Cancer. N Engl J Med. 2025;393(11):1051-1064.