The Protein Encoded by the CCDC170 Breast Cancer Gene Functions to Organize the Golgi-Microtubule Network

Abstract

Genome-Wide Association Studies (GWAS) and subsequent fine-mapping studies (> 50) have implicated single nucleotide polymorphisms (SNPs) located at the CCDC170/C6ORF97-ESR1 locus (6q25.1) as being associated with the risk of breast cancer. Surprisingly, our analysis using genome-wide differential allele-specific expression (DASE), an indicator for breast cancer susceptibility, suggested that the genetic alterations of CCDC170, but not ESR1, account for GWAS-associated breast cancer risk at this locus. Breast cancer-associated CCDC170 nonsense mutations and rearrangements have also been detected, with the latter being specifically implicated in driving breast cancer. Here we report that the wild type CCDC170 protein localizes to the region of the Golgi apparatus and binds Golgi-associated microtubules (MTs), and that breast cancer-linked truncations of CCDC170 result in loss of Golgi localization. Overexpression of wild type CCDC170 triggers Golgi reorganization, and enhances Golgi-associated MT stabilization and acetyltransferase ATAT1-dependent α-tubulin acetylation. Golgi-derived MTs regulate cellular polarity and motility, and we provide evidence that dysregulation of CCDC170 affects polarized cell migration. Taken together, our findings demonstrate that CCDC170 plays an essential role in Golgi-associated MT organization and stabilization, and implicate a mechanism for how perturbations in the CCDC170 gene may contribute to the hallmark changes in cell polarity and motility seen in breast cancer.

Large-scale investigation of the reasons why potentially important genes are ignored

“…While our analysis shows that this biological characteristic is generally associated with a low number of publications, the absence of TERT restricts excess cell proliferation [ 38 ]—a factor that overcomes the difficulty in its study following its ectopic activation. Another interesting illustration is provided by the poorly studied breast cancer gene CCDC170, which encodes for one of the most charged and acidic human proteins but also appears to have some structural role in maintaining the organization of Golgi-associated microtubules [ 39 ]. As a final illustration, consider C1orf106, a gene with the second-strongest genetic association to ulcerative colitis.…”

Risk variant in miR-544a binding site in CCDC170 is associated with osteoporosis

“…Our study provided a possible mechanism for this, in that upregulation of miR-544a resulted in decreased CCDC170 expression in osteoporosis. Multiple studies have found that CCDC170 plays an important role in breast cancer [18,19] and multiple genome-wide linkage scans have shown that CCDC170 is one of the genes most strongly linked to BMD. However, no in vivo or in vitro experiments have directly verified the role of CCDC170 .…”

Expression of Coiled-Coil Domain Containing 34 (CCDC34) and its Prognostic Significance in Pancreatic Adenocarcinoma

“…The spatial folding of coiled-coil domain-containing (CCDC) is variable, resulting in different spatial conformations, achieving many different molecular biological functions, including regulating gene expression, cell division, membrane fusion and drug controlled release [ 10 ]. It has previously been confirmed that the CCDC gene structure or the epigenetic changes associated with many malignant tumors and aberrant expression CCDC related protein have been demonstrated in nasopharyngeal carcinoma [ 11 ], breast cancer [ 12 , 13 ], non-small cell lung cancer (NSCLC) [ 14 , 15 ], gastric cancer [ 16 , 17 ], colorectal cancer [ 18 ] and hepatocellular carcinoma [ 19 , 20 ]. Recently, CCDC34, as a new member of CCDC related protein family, has been shown to be overexpressed in bladder carcinoma, and knockdown of its expression has been shown to inhibit the invasion and migration of tumor cells [ 7 ].…”