Carcinogenesis Advance Access originally published online on October 27, 2006
Carcinogenesis 2007 28(3):749-759; doi:10.1093/carcin/bgl202
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Securin induces genetic instability in colorectal cancer by inhibiting double-stranded DNA repair activity
1 Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham B15 2TH, UK
2 Department of Cellular Pathology (Histopathology), University of Birmingham UK
3 University Hospital Birmingham Trust Birmingham, UK
4 CRUK Institute for Cancer Studies, University of Birmingham UK
*To whom correspondence should be addressed. Tel:+44 121 415 8714; Fax: +44 121 415 8712; Email: mccabcjz{at}bham.ac.uk
Genetic instability (GI) is a hallmark feature of tumor development. Securin, also known as pituitary tumor transforming gene (PTTG), is a mitotic checkpoint protein which is highly expressed in numerous cancers, is associated with tumor invasiveness, and induces GI in thyroid cells. We used fluorescence inter-simple sequence repeat PCR to assess GI caused primarily by DNA breakage events in 19 colorectal tumors. GI values ranged significantly, with Dukes' stage C&D colorectal tumors exhibiting greater GI and higher securin expression than Dukes' stage A&B tumors. Consistent with these findings, we observed a dose-dependent increase in GI in HCT116 cells in response to securin overexpression, as well as in non-transformed human fibroblasts. As securin has been implicated in a novel DNA repair pathway in fission yeast, we investigated its potential role in chemotoxic DNA damage response pathways in mammalian cells, using host cell reactivation assays. Securin overexpression in HCT116 cells inhibited etoposide-induced double-stranded DNA damage repair activity, and repressed Ku heterodimer function. Additionally, we observed that securin and Ku70 showed a reciprocal cytosol–nuclear translocation in response to etoposide-induced dsDNA damage. Our data suggest that, by repressing Ku70 activity and inhibiting the non-homologous end-joining dsDNA repair pathway, securin may be a critical gene in the development of GI in colorectal cancer.
Abbreviations: DSB, double-strand break; dsDNA, double-stranded DNA; FISSR-PCR, fluorescence inter-simple sequence repeat polymerase chain reaction; GI, genetic instability; PK-DNA, protein kinase-dependent DNA repair; PTTG, pituitary tumor transforming gene; RLU, relative light units; VO, vector-only
Received May 18, 2006; revised October 11, 2006; accepted October 14, 2006.
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