CCN5, a Novel Transcriptional Repressor of the Transforming Growth Factor β Signaling Pathway

Abstract

CCN5 is a member of the CCN (connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed) family and was identified as an estrogen-inducible gene in estrogen receptor-positive cell lines. However, the role of CCN5 in breast carcinogenesis remains unclear. We report here that the CCN5 protein is localized mostly in the cytoplasm and in part in the nucleus of human tumor breast tissue. Using a heterologous transcription assay, we demonstrate that CCN5 can act as a transcriptional repressor presumably through association with histone deacetylase 1 (HDAC1). Microarray gene expression analysis showed that CCN5 represses expression of genes associated with epithelial-mesenchymal transition (EMT) as well as expression of key components of the transforming growth factor β (TGF-β) signaling pathway, prominent among them TGF-βRII receptor. We show that CCN5 is recruited to the TGF-βRII promoter, thereby providing a mechanism by which CCN5 restricts transcription of the TGF-βRII gene. Consistent with this finding, CCN5, we found, functions to suppress TGF-β-induced transcriptional responses and invasion that is concomitant with EMT. Thus, our data uncovered CCN5 as a novel transcriptional repressor that plays an important role in regulating tumor progression functioning, at least in part, by inhibiting the expression of genes involved in the TGF-β signaling cascade that is known to promote EMT.

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ACKNOWLEDGMENTS

We thank Azeddine Atfi and Jan Mester for the critical review of the manuscript and Pauline Sabbah for technical assistance.

This work was supported by Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, the Ligue Nationale contre le Cancer (Comité de Paris), and the Groupement d'Entreprises Françaises dans la Lutte contre le Cancer. Olivier De Wever is supported by a postdoctoral grant from Fund for Scientific Research-Flanders.