Securin induces genetic instability in colorectal cancer by inhibiting double-stranded DNA repair activity

Abstract

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.

p21 Cip1 restrains pituitary tumor growth

“…Both loss of Pttg and Pttg overexpression result in aneuploidy (here and in refs. 22 and 26), and Pttg overexpression triggers genetic instability characterized by DNA breakage (20,21,44). Whether aneuploidy is the cause of DNA damage signaling-pathway activation remains unproven, but both processes activate p21 expression (33).…”

Acromegaly pathogenesis and treatment

“…Pttg mediates in vitro transformation and in vivo tumorigenesis in mice, and PTTG overexpression induces aneuploidy with dysregulated G 2 /M checkpoint surveillance, resulting in abnormal mitosis and chromosomal instability (65). PTTG modulates p53, participating in DNA damage/repair and apoptosis (66)(67)(68). PTTG is abundantly expressed in pituitary adenomas (69) and correlates with tumor invasiveness and recurrence; it is induced early in estrogen-induced pituitary tumorigenesis.…”

Transcriptional targets for pituitary tumor-transforming gene-1

“…PTTG1 induces chromosome instability through binding to separase and regulating sister chromosome separation (Waizenegger et al 2002). PTTG1 also induces genetic instability by inhibiting DNA damage repair through interfering with Ku heterodimer formation (Kim et al 2007a). PTTG1, as a transcription factor, can directly and indirectly induce expression of genes that are involved in regulating tumorigenesis and cancer development.…”