Systems Pharmacogenomics Finds RUNX1 Is an Aspirin-Responsive Transcription Factor Linked to Cardiovascular Disease and Colon Cancer

Abstract

Aspirin prevents cardiovascular disease and colon cancer; however aspirin's inhibition of platelet COX-1 only partially explains its diverse effects. We previously identified an aspirin response signature (ARS) in blood consisting of 62 co-expressed transcripts that correlated with aspirin's effects on platelets and myocardial infarction (MI). Here we report that 60% of ARS transcripts are regulated by RUNX1 – a hematopoietic transcription factor - and 48% of ARS gene promoters contain a RUNX1 binding site. Megakaryocytic cells exposed to aspirin and its metabolite (salicylic acid, a weak COX-1 inhibitor) showed up regulation in the RUNX1 P1 isoform and MYL9, which is transcriptionally regulated by RUNX1. In human subjects, RUNX1 P1 expression in blood and RUNX1-regulated platelet proteins, including MYL9, were aspirin-responsive and associated with platelet function. In cardiovascular disease patients RUNX1 P1 expression was associated with death or MI. RUNX1 acts as a tumor suppressor gene in gastrointestinal malignancies. We show that RUNX1 P1 expression is associated with colon cancer free survival suggesting a role for RUNX1 in aspirin's protective effect in colon cancer. Our studies reveal an effect of aspirin on RUNX1 and gene expression that may additionally explain aspirin's effects in cardiovascular disease and cancer.

Transcription Factor RUNX1 Regulates Platelet PCTP (Phosphatidylcholine Transfer Protein): Implications for Cardiovascular Events

“…Thus, higher PCTP expression is associated with a higher risk of cardiovascular events. In a separate CATHGEN analysis, 16 we previously showed that RUNX1 P1 probe sets (233690_at and 220918_at) are significantly lower in CATHGEN patients who develop death or MI. Of the RUNX1 P2 probe sets described above, one 211181_x_at was associated with higher risk of death/MI in CATHGEN (OR = 3.3 [1.5–7.3], p-value = 0.003.…”

“…Several potential probe sets available on the Affymetrix microarray map to the RUNX1 locus on chromosome 21. Of the 17 available probe sets, we selected 6 that map to a single locus in the genome and had evidence by PCR for being able to discriminate between RUNX1 P1 vs. P2 expression by PCR (Supplemental Table 5) as previously described 16,27 . To select microarray probe sets for RUNX1 we used banked, serial peripheral blood RNA from healthy volunteers with matched microarray data 27 and performed PCR for RUNX1 isoforms.…”

“…To select microarray probe sets for RUNX1 we used banked, serial peripheral blood RNA from healthy volunteers with matched microarray data 27 and performed PCR for RUNX1 isoforms. 16 Linear mixed-effects regression with a random effect for subject was used to model the linear relationship between RUNX1 probe set expression and RUNX1 PCR expression. Effect sizes, standard errors, and p-values (calculated using a normal approximation) are reported.…”

“…and A.K. Rao, M.B.B.S., unpublished data, 2017) and human erythroleukemia (HEL) cells 16 express both variants. Human RUNX1 haplodeficiency is associated with thrombocytopenia, platelet function defects, and increased risk of leukemia and myelodysplastic syndromes.…”

MiR-1202 functions as a tumor suppressor in glioma cells by targeting Rab1A

“…[23][24][25] Growing evidence has revealed that miRNAs play an important role in carcinogenesis and cancer progression. Depending on their mRNA targets, miRNAs can act as oncogenes or tumor suppressor genes.…”