Aspirin mediates histone methylation that inhibits inflammation-related stemness gene expression to diminish cancer stemness via COX-independent manner

Abstract

Background: The widely recognized anti-cancer potential of aspirin has created a broad interest to explore the clinical benefits of aspirin in cancer therapy. However, the current understanding of the molecular mechanisms involved in the anti-cancer potential of aspirin remains limited. Methods: Cancer stemness assays which contained ALDH, side population, chemo-resistance, sphere formation, and tumorigenesis were performed to validate aspirin function in vitro and in vivo. Histone modification assay was performed to check the effect of aspirin on histone methylation as well as the activity of HDAC and KDM6A/B. Inhibitor in vivo assay was performed to evaluate therapeutic effects of various inhibitor combination manners. Results: In regards to in vitro studies, aspirin diminishes cancer cell stemness properties which include reducing the ALDH+ subpopulation, side population, chemo-resistance, and sphere formation in three cancer types. In regards to in vivo studies, aspirin decreases tumor growth and metastasis and prolongs survival. In addition, our results showed that aspirin inhibits inflammation-related stemness gene expression (especially ICAM3) identified by a highthroughput siRNA platform. In regards to the underlying molecular mechanism of action, aspirin reduces histone demethylase (KDM6A/B) expression that mediates histone methylation and suppresses gene expression via a COXindependent manner. In regards to therapeutic strategies, aspirin combined HDM inhibitors, ICAM3 downstream signaling Src/PI3K inhibitors, or ICAM3 inhibitor Lifitigrast prevents cancer progression in vivo. Conclusions: The aforementioned findings suggest a molecular model that explains how aspirin diminishes cancer cell stemness properties. These findings may provide novel targets for therapeutic strategies involving aspirin in the prevention of cancer progression.

Cellular Metabolomics Profiles Associated With Drug Chemosensitivity in AML

“…Intriguingly, as mentioned above, asprin decreases the blood levels of several metabolites when cross checked with the human metabolome database. Our results are concordant with multiple reports showing that aspirin can suppress chemoresistance in various malignancies (27)(28)(29)(30)(31)(32). A clinical trial is currently evaluating the efficacy of aspirin and tamoxifen in combination with doxorubicin as part of standard AC-T chemotherapy for treatment of high risk ER+ or ER-breast cancer (NCT04038489 clinicaltrials.gov).…”

TIFA promotes colorectal cancer cell proliferation in an RSK‐ and PRAS40‐dependent manner

“…A value of P < 0.05 was used as the criterion for statistical signi cance. *Indicates signi cant difference with P < 0.05, **indicates signi cant difference with P < 0.01, ***indicates signi cant difference with P < 0.001 [32,34,35].…”

Looking at NSAIDs from a historical perspective and their current status in drug repurposing for cancer treatment and prevention

“…In the same study, cell-based analyses also showed that increasing doses of aspirin reduced the cancer cell viability along with long-term clonogenesis while affecting caspase-3 activity minimally (Der et al 2020 ). Besides, Zhang et al ( 2020a , b ) showed that aspirin reduced the protein levels of programmed cell death-ligand 1 (PD-L1) which is expressed in tumor cells and displays an inhibitory role in antitumor immunity in A549 and H1299 human lung cancer cell lines. Further, the promoter of PD-L1 was cloned in a luciferase reporter pGL3-basic plasmid and aspirin was shown to reduce luciferase activity of pGL3-PD-L1.…”

“…(Zhang et al 2020b ). In the study of Zhang et al ( 2020a , b ), changes in ALDH + subpopulation were investigated by using ALDH staining in A549 lung, MDA-MB231 breast, and HepG2 hepatocellular cancer cell lines. Aspirin reduced the ALDH + subpopulation along with an increase in apoptosis and a decrease in sphere formation.…”

“…Aspirin reduced the ALDH + subpopulation along with an increase in apoptosis and a decrease in sphere formation. Aspirin also inhibited inflammation-related stemness gene expression, especially ICAM3 (Zhang et al 2020a )].…”