Deepak Voora, MD, A. Koneti Rao, MD, Gauthami S. Jalagadugula, PhD, Rachel Myers, PhD, Emily Harris, Thomas L. Ortel, MD PhD, Geoffrey S. Ginsburg, MD PhD. 2016. Systems Pharmacogenomics Finds RUNX1 Is an Aspirin-Responsive Transcription Factor Linked to Cardiovascular Disease and Colon Cancer. EBioMedicine..
a Duke Center for Applied Genomics & Precision Medicine, Duke University, Durham, NC, United States
b Department of Medicine, Duke University, Durham, NC, United States
c Department of Medicine and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, United States
Aspirin prevents cardiovascular disease and colon cancer; however aspirin’s inhibition of platelet COX1 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 COX1 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.