CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1

Abstract

RET/papillary thyroid carcinoma 1 (PTC1) oncogene is frequently activated in human PTCs. It is characterized by the fusion of the intracellular kinase-encoding domain of RET to the first 101 amino acids of CCDC6. The aim of our work is to characterize the function of the CCDC6 protein to better understand the function of its truncation, that results in the loss of the expression of one allele, in the process of thyroid carcinogenesis. Here, we report that CCDC6 interacts with CREB1 and represses its transcriptional activity by recruiting histone deacetylase 1 and protein phosphatase 1 proteins at the CRE site of the CREB1 target genes. Finally, we show an increased CREB1 phosphorylation and activity in PTCs carrying the RET/PTC1 oncogene. Consistently, an increased expression of two known CREB1 target genes, AREG and cyclin A, was observed in this subgroup of thyroid papillary carcinomas. Therefore, the repression of CREB1 activity by CCDC6 has a critical function in the development of human thyroid papillary carcinomas carrying RET/PTC1 activation.

Central Role of RET in Thyroid Cancer

“…CCDC6 gene product is a ubiquitously expressed 65 kDa protein that displays proapoptotic activity and is involved in ATM-mediated cellular response to DNA damage (Celetti et al 2004;Merolla et al 2007). A role of CCDC6 in the repression of CREB1, a transcriptional factor essential for thyroid cell growth and differentiation, has also been described (Leone et al 2010). NCOA4 gene encodes a 70 kDa protein that functions as a coactivator of PPARg ( peroxisome-proliferator-activated receptor g) and AR (androgen receptor) (Yeh and Chang 1996;Heinlein et al 1999).…”

Thyroid Cancer: Role of RET and Beyond

“…CCDC6 (coiled-coil domain containing sequence 6, also known as H4/D10S170) gene product is a ubiquitously expressed 65-kDa nuclear and cytosolic protein that has been shown to display proapoptotic activity and to be involved in the ATM-mediated cellular response to DNA damage [72,73]. More recently, a direct role of CCDC6 in the repression of CREB1, a transcriptional factor essential for thyroid cell growth and differentiation, has been described [74]. The CCDC6 gene has been found fused to the PDGFRβ gene in atypical chronic myeloid leukemia and to PTEN tumor suppressor phosphatase in PTCs, indicating its high susceptibility to gene fusion [75,76].…”

miR-130b-3p Upregulation Contributes to the Development of Thyroid Adenomas Targeting <b><i>CCDC6</i></b> Gene

“…The candidate target of miR-130b-3p was the CCDC6 gene, which encodes a coiled-coil domain-containing protein and is ubiquitously expressed and may function as a tumor suppressor. Moreover, this protein is responsible for the transcriptional repression of CREB1 target genes [12]. For the seed sequence, there was a matching sequence in the 3′-UTR of the CCDC6 gene (fig.…”

“…Chromatin samples were processed for ChIP experiments as reported elsewhere [12]. Samples were subjected to immunoprecipitation with the specific CREB1 antibody (Upstate Biotechnology).…”

“…We report that miR-130b-3p is drastically upregulated in the large majority of benign thyroid neoplasias such as FTAs, known to be frequently CREB dependent for proliferation, in comparison with normal thyroid. Interestingly, this miRNA has as a target the CCDC6 gene that our previous studies have demonstrated to code for a protein able to interact with CREB1, leading to the transcriptional repression of CREB1 target genes [12]. …”