Survivin Is A Novel Target Of The Hedgehog/Gli Signaling Pathway In Human Tumor Cell Lines

Survivin, a pivotal antiapoptotic protein is expressed in tumors whereas its expression in normal tissues is extremely low. It is believed that transcription of the survivin gene is driven mainly by the transcription factor Sp1. We have identified 11 potential consensus sites for GLI trancription factors in the survivin promoter, albeit non of them has been a full consensus. Interestingly, the distal part of the promoter (-1765 to -941, ending at +39) containing 4 GLI sites showed about 2-fold higher activity than the proximal promoter (-941 to +39). The survivin promoter-reporter has been found to be upregulated mainly by plasmids encoding GLI2 and deltaN-GLI2, a more active GLI2 truncated mutant. Its activity was even higher than the Sp1 activity. The promoter-reporter plasmid is also inhibited by the GLI1/2 inhibitor GANT61. Moreover, by analyzing 40 human tumor cell lines of various origin, we have found that the endogenous survivin protein level substantially decreases after the incubation with GANT61 in most cell lines. Real-time PCR for the survivin mRNA in GANT61-sensitive cell lines showed a decrease by up to about 50 per cent. These data suggest that survivin may be a novel important target regulated by the Hedgehog/GLI signaling pathway, which has been reported previously to be deregulated in the majority of tumor types. The work was supported by the grant NT/14005 from IGA, Ministry of Health, Czech Republic. Citation Format: Kateřina Vlckova, Lubica Ondrusova, Jiri Reda, Jiri Vachtenheim, Petra Zakova. Survivin is a novel target of the Hedgehog/GLI signaling pathway in human tumor cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2135. doi:10.1158/1538-7445.AM2015-2135