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

被引：210

作者：

Betancur, Paola A. ^{[1
,2
]}

Abraham, Brian J. ^{[3
]}

Yiu, Ying Y. ^{[1
,2
]}

Willingham, Stephen B. ^{[1
,2
]}

Khameneh, Farnaz ^{[1
,2
]}

Zarnegar, Mark ^{[1
,2
]}

Kuo, Angera H. ^{[1
,2
]}

McKenna, Kelly ^{[1
,2
]}

Kojima, Yoko ^{[4
]}

Leeper, Nicholas J. ^{[4
,5
]}

Ho, Po ^{[1
,2
]}

Gip, Phung ^{[1
,2
]}

Swigut, Tomek ^{[1
,2
]}

Sherwood, Richard I. ^{[6
,7
]}

Clarke, Michael F. ^{[1
,2
]}

Somlo, George ^{[8
]}

Young, Richard A. ^{[3
,9
]}

Weissman, Irving L. ^{[1
,2
]}

机构：

[1] Stanford Univ, Sch Med, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA

[2] Stanford Univ, Sch Med, Ludwig Ctr Canc Stem Cell Res & Med, Stanford, CA 94305 USA

[3] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[4] Stanford Univ, Sch Med, Dept Surg, Div Vasc Surg, Stanford, CA 94305 USA

[5] Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA

[6] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA

[7] Harvard Med Sch, Dept Med, Div Genet, Boston, MA 02115 USA

[8] City Hope Natl Med Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA 91010 USA

[9] MIT, Dept Biol, Cambridge, MA 02139 USA

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

美国国家卫生研究院;

关键词：

TNF-ALPHA; TRANSCRIPTION FACTORS; SELECTIVE-INHIBITION; RECEPTOR-ALPHA; CELL IDENTITY; EXPRESSION; DISTINCT; PHAGOCYTOSIS; RESISTANT; DISCOVERY;

D O I：

10.1038/ncomms14802

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

CD47 is a cell surface molecule that inhibits phagocytosis of cells that express it by binding to its receptor, SIRP alpha, 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.

引用

页数：14

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