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

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.

Inflammation, phagocytosis and cancer: another step in the CD47 act

“…Previous studies including breast cancer identified that the promoter region for the CD47 gene is regulated by binding of several transcription factors, including MYC and NF-κB (8,9). However, the exact mechanism behind the overexpression of CD47 in cancer cells is insufficiently understood (10).…”

“…In a recent study published in Nature Communications by Betancur et al, a CD47-associated specific regulatory genomic locus, a so-called "super-enhancer" (SE), was identified (10). In general, a SE constitutes a gene region with strong enrichment of transcriptional co-activators as mediator (MED1) (11).…”

“…SEs are regarded as a specific feature gained by tumour cells, since they are absent in normal tissue (10). They comprise several clusters of normal enhancers, the so-called constituent enhancers (10). Correspondent to their function, SEs are preferentially located near oncogenes or gene regions rearranged by translocation (12 (10).…”

“…In general, a SE constitutes a gene region with strong enrichment of transcriptional co-activators as mediator (MED1) (11). Typically, an accumulation of H3K27ac, a modification of the DNA packaging protein H3, is also present and indicates regions of active chromatin (10). Any of these factors may be used to define a SE that usually covers an area of >20 kilobases (kb), thus measuring a multitude of a "normal" enhancer (11).…”

“…Any of these factors may be used to define a SE that usually covers an area of >20 kilobases (kb), thus measuring a multitude of a "normal" enhancer (11). SEs are regarded as a specific feature gained by tumour cells, since they are absent in normal tissue (10). They comprise several clusters of normal enhancers, the so-called constituent enhancers (10).…”