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

• Published in: EBioMedicine Vol. 11; no. C; pp. 157 - 164
• Main Authors: Voora, Deepak, Rao, A. Koneti, Jalagadugula, Gauthami S., Myers, Rachel, Harris, Emily, Ortel, Thomas L., Ginsburg, Geoffrey S.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2016; Elsevier
• Subjects: Advanced Basic Science; Aspirin; Aspirin - pharmacology; Aspirin - therapeutic use; Blood Platelets - metabolism; Cardiovascular disease; Cardiovascular Diseases - genetics; Cardiovascular Diseases - metabolism; Cell Line, Tumor; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - mortality; Colonic Neoplasms - pathology; Colorectal cancer; Core Binding Factor Alpha 2 Subunit - genetics; Core Binding Factor Alpha 2 Subunit - metabolism; Gene Expression Profiling; Gene Expression Regulation - drug effects; Genetic Predisposition to Disease; Humans; Internal Medicine; Megakaryocytes - drug effects; Megakaryocytes - metabolism; Neoplasm Staging; Pharmacogenetics; Prognosis; Research Paper; RUNX1; Systems pharmacogenomics; Cardiovascular disease; Aspirin; Systems pharmacogenomics; Gene expression profiling; Colorectal cancer; RUNX1
• DOI: 10.1016/j.ebiom.2016.08.021
• ISSN: 2352-3964

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. •Aspirin regulates RUNX1 gene expression and the expression of RUNX1-regulated platelet proteins•RUNX1 gene expression in blood is associated with death and myocardial infarction in patients with cardiovascular disease•RUNX1 expression in colon cancers is associated with cancer free survival Aspirin is among the most commonly used medications to prevent cardiovascular disease and colon cancer. Here we describe a property of aspirin that affects a gene named RUNX1 that is important in regulating platelets – the cells that form blood clots that cause heart attack and stroke – and in colon cancer. We go on to show that levels of RUNX1 are informative of which patients with cardiovascular disease will have future heart attacks and which patients with colon cancer will die from their cancers. This property of aspirin helps to explain how a drug like aspirin can produce such diverse effects.