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The tumour suppressor C/EBPδ inhibits FBXW7 expression and promotes mammary tumour metastasis
Author(s) -
Balamurugan Kuppusamy,
Wang JuMing,
Tsai HsinHwa,
Sharan Shikha,
Anver Miriam,
Leighty Robert,
Sterneck Esta
Publication year - 2010
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2010.280
Subject(s) - metastasis , library science , cancer , biology , cancer research , genetics , computer science
Inflammation and hypoxia are known to promote the metastatic progression of tumours. The CCAAT/enhancer‐binding protein‐δ ( C/EBP δ, CEBPD ) is an inflammatory response gene and candidate tumour suppressor, but its physiological role in tumourigenesis in vivo is unknown. Here, we demonstrate a tumour suppressor function of C/EBPδ using transgenic mice overexpressing the Neu/Her2/ERBB2 proto‐oncogene in the mammary gland. Unexpectedly, this study also revealed that C/EBPδ is necessary for efficient tumour metastasis. We show that C/EBPδ is induced by hypoxia in tumours in vivo and in breast tumour cells in vitro , and that C/EBPδ‐deficient cells exhibit reduced glycolytic metabolism and cell viability under hypoxia. C/EBPδ supports CXCR4 expression. On the other hand, C/EBPδ directly inhibits expression of the tumour suppressor F‐box and WD repeat‐domain containing 7 gene ( FBXW7, FBW7, AGO, Cdc4 ), encoding an F‐box protein that promotes degradation of the mammalian target of rapamycin ( mTOR ). Consequently, C/EBPδ enhances mTOR/AKT/S6K1 signalling and augments translation and activity of hypoxia‐inducible factor‐1α ( HIF‐1α ), which is necessary for hypoxia adaptation. This work provides new insight into the mechanisms by which metastasis‐promoting signals are induced specifically under hypoxia.