Systems Pharmacogenomics Finds RUNX1 Is an Aspirin-Responsive Transcription Factor Linked to Cardiovascular Disease and Colon Cancer
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'...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-09-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S235239641630370X |
| _version_ | 1818940702990532608 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Deepak Voora, MD |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T06:43:51Z |
| format | Article |
| id | doaj.art-11b9c39f0a6042bb84f1bf5df2994d94 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-20T06:43:51Z |
| publishDate | 2016-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-11b9c39f0a6042bb84f1bf5df2994d942022-12-21T19:49:46ZengElsevierEBioMedicine2352-39642016-09-0111C15716410.1016/j.ebiom.2016.08.021Systems Pharmacogenomics Finds RUNX1 Is an Aspirin-Responsive Transcription Factor Linked to Cardiovascular Disease and Colon CancerDeepak Voora, MD0A. Koneti Rao, MD1Gauthami S. Jalagadugula, PhD2Rachel Myers, PhD3Emily Harris4Thomas L. Ortel, MD, PhD5Geoffrey S. Ginsburg, MD, PhD6Duke Center for Applied Genomics & Precision Medicine, Duke University, Durham, NC, United StatesDepartment of Medicine and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, United StatesDepartment of Medicine and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, United StatesDuke Center for Applied Genomics & Precision Medicine, Duke University, Durham, NC, United StatesDuke Center for Applied Genomics & Precision Medicine, Duke University, Durham, NC, United StatesDepartment of Medicine, Duke University, Durham, NC, United StatesDuke Center for Applied Genomics & Precision Medicine, Duke University, Durham, NC, United StatesAspirin 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.http://www.sciencedirect.com/science/article/pii/S235239641630370XAspirinSystems pharmacogenomicsCardiovascular diseaseColorectal cancerGene expression profilingRUNX1 |
| spellingShingle | 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 Systems Pharmacogenomics Finds RUNX1 Is an Aspirin-Responsive Transcription Factor Linked to Cardiovascular Disease and Colon Cancer EBioMedicine Aspirin Systems pharmacogenomics Cardiovascular disease Colorectal cancer Gene expression profiling RUNX1 |
| title | Systems Pharmacogenomics Finds RUNX1 Is an Aspirin-Responsive Transcription Factor Linked to Cardiovascular Disease and Colon Cancer |
| title_full | Systems Pharmacogenomics Finds RUNX1 Is an Aspirin-Responsive Transcription Factor Linked to Cardiovascular Disease and Colon Cancer |
| title_fullStr | Systems Pharmacogenomics Finds RUNX1 Is an Aspirin-Responsive Transcription Factor Linked to Cardiovascular Disease and Colon Cancer |
| title_full_unstemmed | Systems Pharmacogenomics Finds RUNX1 Is an Aspirin-Responsive Transcription Factor Linked to Cardiovascular Disease and Colon Cancer |
| title_short | Systems Pharmacogenomics Finds RUNX1 Is an Aspirin-Responsive Transcription Factor Linked to Cardiovascular Disease and Colon Cancer |
| title_sort | systems pharmacogenomics finds runx1 is an aspirin responsive transcription factor linked to cardiovascular disease and colon cancer |
| topic | Aspirin Systems pharmacogenomics Cardiovascular disease Colorectal cancer Gene expression profiling RUNX1 |
| url | http://www.sciencedirect.com/science/article/pii/S235239641630370X |
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