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 ␤ (TGF-␤) signaling pathway, prominent among them TGF-␤RII receptor. We show that CCN5 is recruited to the TGF-␤RII promoter, thereby providing a mechanism by which CCN5 restricts transcription of the TGF-␤RII gene. Consistent with this finding, CCN5, we found, functions to suppress TGF-␤-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-␤ signaling cascade that is known to promote EMT.CCN5 (previously known as WISP-2) is a 29-kDa protein member of the connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed (CCN) family (2, 5, 23). The CCN family is composed of six members grouped on the basis of similar structural analogies (7). CCN proteins appear to play important roles in several biological processes, including cell growth, adhesion, and migration as well as numerous endocrine-regulated functions (9,39,41). CCN proteins encompass four structural domains: an insulin-like growth factor-binding protein (IGF-BP) domain, a von Willebrand factor type C (VWC) domain, a thrombospondin (TSP-1) domain, and a cysteine knot (CT) domain reported to act as a potential proliferation module (29). Although the physiological function of CCN5 is not well defined, its domain structure suggests that its function may be different from that of other members of the CCN family. CCN5 contains only three structural domains and lacks the CT domain (7,8,35). It has been shown that CCN5 suppresses proliferation and its expression is reduced in cancers (14,31,35). Previously, we showed that upon hormone binding, the estrogen receptor (ER) directly regulates the ccn5 gene in all ER-positive breast cancer cell lines tested (17). Moreover, we found that CCN5 knockdown not only induced estradiol-independent growth of these cells, owing to a loss of estrogen receptor ␣ (ER␣) expression, but also promoted epithelial-mesenchymal transition (EMT) (18), a process involved in tumor invasiveness and metastasis (13,43,46,51).Consistent with its role in tumor progression, our recent studies have shown that CCN5 is ...

Anti-fibrotic effect of CCN3 accompanied by altered gene expression profile of the CCN family

“…It is reported that CCN3 is present in the nucleus and behaves like a transcription factor therein (Planque et al 2006). Of our interest, CCN5, another CCN family member, actually regulates gene expression in the nucleus (Sabbah et al 2011). Investigation of the mechanism of this CCN3 action is of great scientific interest as well.…”

Longitudinal muscle gene expression patterns associated with differential intramuscular fat in cattle

“…It has recently been discovered to encode a novel secreted adipokine protein that is a negative regulator of preadipocyte commitment (Hammarstedt et al, 2013). It has also been shown to inhibit the pro-fibrotic connective tissue growth factor (Sabbah et al, 2011). Furthermore, WISP2 was recently identified as one of the top candidate secreted proteins in the development of obesity, as determined by fat depot DE between obese and lean humans (Dahlman et al, 2012).…”

Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats

“…24 WNT1-inducible-signaling pathway protein 2 (WISP-2) (CCN5), a component of the Wnt pathway, mediates growth arrest and blunts TGF-b-induced effects. 25,26 The present study addresses the cellular effects of atorvastatin on hepatic MFB in vitro and in vivo with special emphasis on proliferation, apoptosis and senescence.…”