title: 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.
authors: Duke Center for Applied Genomics & Precision Medicine, Duke University, Durham, NC, United States; Department of Medicine, Duke University, Durham, NC, United States. Electronic address: deepak.voora@duke.edu.
authors: Deepak
authors: D
authors: Voora
authors: Department of Medicine and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, United States.
authors: A Koneti
authors: AK
authors: Rao
authors: Department of Medicine and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, United States.
authors: Gauthami S
authors: GS
authors: Jalagadugula
authors: Duke Center for Applied Genomics & Precision Medicine, Duke University, Durham, NC, United States.
authors: Rachel
authors: R
authors: Myers
authors: Duke Center for Applied Genomics & Precision Medicine, Duke University, Durham, NC, United States.
authors: Emily
authors: E
authors: Harris
authors: Department of Medicine, Duke University, Durham, NC, United States.
authors: Thomas L
authors: TL
authors: Ortel
authors: Duke Center for Applied Genomics & Precision Medicine, Duke University, Durham, NC, United States; Department of Medicine, Duke University, Durham, NC, United States. Electronic address: geoffrey.ginsburg@duke.edu.
authors: Geoffrey S
authors: GS
authors: Ginsburg
mesh_terms: D001241:Aspirin / Q000494:pharmacology* / Q000627:therapeutic use; D001792:Blood Platelets / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism; D009367:Neoplasm Staging; D010597:Pharmacogenetics; D011379:Prognosis
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D001241:Aspirin
keywords: Aspirin; Cardiovascular disease; Colorectal cancer; Gene expression profiling; RUNX1; Systems pharmacogenomics