The tumour suppressor C/EBPδ inhibits FBXW7 expression and promotes mammary tumour metastasis

Abstract

Inflammation and hypoxia are known to promote the metastatic progression of tumours. The CCAAT/enhancerbinding protein-d (C/EBPd, 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/EBPd using transgenic mice overexpressing the Neu/Her2/ERBB2 proto-oncogene in the mammary gland. Unexpectedly, this study also revealed that C/EBPd is necessary for efficient tumour metastasis. We show that C/EBPd is induced by hypoxia in tumours in vivo and in breast tumour cells in vitro, and that C/EBPd-deficient cells exhibit reduced glycolytic metabolism and cell viability under hypoxia. C/EBPd supports CXCR4 expression. On the other hand, C/EBPd 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/EBPd enhances mTOR/AKT/S6K1 signalling and augments translation and activity of hypoxia-inducible factor-1a (HIF-1a), which is necessary for hypoxia adaptation. This work provides new insight into the mechanisms by which metastasis-promoting signals are induced specifically under hypoxia.

F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous manner

“…Most previous studies have focused on the tumor-suppressive role of FBXW7 in tumor cells themselves. The putative tumor suppressor C/EBPδ was shown to inhibit FBXW7 expression and to promote mammary tumor metastasis through attenuation of FBXW7-dependent degradation of mTOR in tumor cells (52). We have now discovered what we believe to be a new aspect of FBXW7 function in tumor suppression -namely, its role in the host environment to suppress cancer metastasis.…”

HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells

“…Increased CEBPD participates in the transcription of peroxisome proliferator-activated nuclear receptor g 2 (PPARG2), an adipogenic and proapoptotic inducer, and DNA-damage-inducible protein 153 (GADD153, also known as CHOP), a proapoptotic inducer (13,14). A recent study demonstrated that loss of CEBPD might contribute to the initiation of breast cancer (15). Moreover, inactivated CEBPD was observed in HCC and cervical cancer via an epigenetic effect (16).…”

Promotional effect of microRNA-194 on breast cancer cells via targeting F-box/WD repeat-containing protein 7

“…F-box/WD repeat-containing protein 7 (Fbxw-7), is a tumor suppressor that has been demonstrated to regulate several oncoproteins (10) including, cyclin D, cyclin E (11-13), c-Myc (14,15), aurora kinase A (16), Notch (17)(18)(19)(20) and the proto-oncogene c-Jun (21,22) c-Jun, an extensively-studied member of the JUN family, has been associated with cell proliferation, tumor cell survival and apoptosis (23). Therefore, it is important to investigate the Fbxw-7-associated signaling pathways involved in the proliferation of breast cancer.…”