Nuclear endonuclease G controls cell proliferation in ovarian cancer.

Ovarian cancer is characterized by a high degree of genetic heterogeneity. Platinum-based chemotherapy and some gene-targeted therapies have shown limited treatment efficacy due to toxicity and recurrence, and thus, it is essential to identify additional therapeutic targets based on an understanding of the pathological mechanism. Here, we report that endonuclease G, which exhibits altered expression in ovarian cancer, does not function as a cell death effector that digests chromosomal DNA in ovarian cancer. Endonuclease G is modulated by intracellular reactive oxygen species dynamics and plays a role in cell proliferation in ovarian cancer, suggesting that targeting endonuclease G alone or in combination with other antitumor agents may have the potential for development into a treatment for endonuclease G-overexpressing cancers, including ovarian cancer.

Stabilization of C-terminal binding protein 2 by cellular inhibitor of apoptosis protein 1 via BIR domains without E3 ligase activity.

C-terminal binding protein 2 (CtBP2) is a transcriptional co-repressor that regulates many genes involved in normal cellular events. Because CtBP2 overexpression has been implicated in various human cancers, its protein levels must be precisely regulated. Previously, we reported that CtBP1 and CtBP1-mediated transcriptional repression are regulated by X-linked inhibitor of apoptosis protein (XIAP). In the present study, we sought to investigate whether CtBP2 is also regulated by XIAP or any other human IAP. We found that cIAP1 interacts with CtBP2 via through BIR domains to regulates the steady-state levels of CtBP2 protein in the nucleus. The levels of CtBP2 were gradually increased upon cIAP1 overexpression and downregulated upon cIAP1 depletion. Interestingly, the RING domain of cIAP1 responsible for E3 ligase activity was not required for this regulation. Finally, the levels of CtBP2 modulated by cIAP1 affected the transcription of CtBP2 target genes and subsequent cell migration. Taken together, our data demonstrate a novel function of cIAP1 which involves protecting CtBP2 from degradation to stabilize its steady-state level. These results suggest that cIAP1 might be a useful target in strategies aiming to downregulate the steady-state level of CtBP2 protein in treating human cancers.