A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer

Paola A. Betancur (), Brian J. Abraham, Ying Y. Yiu, Stephen B. Willingham, Farnaz Khameneh, Mark Zarnegar, Angera H. Kuo, Kelly McKenna, Yoko Kojima, Nicholas J. Leeper, Po Ho, Phung Gip, Tomek Swigut, Richard I. Sherwood, Michael F. Clarke, George Somlo, Richard A. Young () and Irving L. Weissman ()
Additional contact information
Paola A. Betancur: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine
Brian J. Abraham: Whitehead Institute for Biomedical Research
Ying Y. Yiu: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine
Stephen B. Willingham: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine
Farnaz Khameneh: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine
Mark Zarnegar: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine
Angera H. Kuo: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine
Kelly McKenna: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine
Yoko Kojima: Stanford University School of Medicine
Nicholas J. Leeper: Stanford University School of Medicine
Po Ho: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine
Phung Gip: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine
Tomek Swigut: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine
Richard I. Sherwood: Brigham and Women's Hospital and Harvard Medical School
Michael F. Clarke: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine
George Somlo: City of Hope National Medical Center
Richard A. Young: Whitehead Institute for Biomedical Research
Irving L. Weissman: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract CD47 is a cell surface molecule that inhibits phagocytosis of cells that express it by binding to its receptor, SIRPα, on macrophages and other immune cells. CD47 is expressed at different levels by neoplastic and normal cells. Here, to reveal mechanisms by which different neoplastic cells generate this dominant ‘don’t eat me’ signal, we analyse the CD47 regulatory genomic landscape. We identify two distinct super-enhancers (SEs) associated with CD47 in certain cancer cell types. We show that a set of active constituent enhancers, located within the two CD47 SEs, regulate CD47 expression in different cancer cell types and that disruption of CD47 SEs reduces CD47 gene expression. Finally we report that the TNF-NFKB1 signalling pathway directly regulates CD47 by interacting with a constituent enhancer located within a CD47-associated SE specific to breast cancer. These results suggest that cancers can evolve SE to drive CD47 overexpression to escape immune surveillance.

Date: 2017
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DOI: 10.1038/ncomms14802

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