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12th World Cancer Conference

London, UK

Jiri Vachtenheim

Jiri Vachtenheim

Charles University in Prague, Czech Republic

Title: GLI2, a Hedgehog signaling pathway effector, is a transcription activator of survivin expression in human tumor cells

Biography

Biography: Jiri Vachtenheim

Abstract

GLI transcription factors are eff ectors of the Hedgehog/GLI signaling pathway but can act also independently of the upstream signals due to their activation by several signaling pathways deregulated in cancer cells. Th ey have an important role in the maintenance of the tumor stemness. Survivin (a “tumor protein”) levels in tumors cells are invariably high, whereas its expression
is absent or extremely low in normal tissues. Th e general mechanism of its high and specifi c expression in tumor tissue remained unclear. Here, we identifi ed survivin as a target of GLI2 and found many putative consensus binding sites for GLI transcription factors in the survivin promoter. Inhibitors of the Hedgehog/GLI pathway, cyclopamine and GANT61, decreased the survivin promoter activity in reporter assays. GANT61, a low molecular weight GLI1/2 inhibitor, repressed endogenous survivin protein and mRNA
expression levels in most cells across a large panel of tumor cell lines, while expression of genes such as SRC or BCL2 were nor changed. Chromatin immunoprecipitation showed GLI2 binding to the survivin promoter. Moreover, aft er transfection of ectopic GLI2 into normal human fi broblasts IMR90 which reveal no survivin or GLI2 expression, the endogenous survivin was evoked in these cells. Th e immunohistochemistry of human lung adenocarcinomas and other tumors revealed a correlation between the tissue
regions showing strong GLI2 and survivin positivity. As the Hedgehog pathway is upregulated in all types of cancer cells, these findings substantially contribute to the explanation of uniform survivin expression in tumors.