SUPRESSOR OF FUSED, A NOVEL COACTIVATOR OF GLI, PROMOTES HEDGEHOG ONCOGENIC FUNCTION IN PANCREATIC CANCER CELLS

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GLI transcription factors have recently elicited significant attention as key effectors of the oncogenic activity of Hedgehog (HH) signaling in pancreatic cancer cells. GLI proteins mediate HH cancer-associated functions by regulating the expression of its downstream target genes. Therefore, knowledge of the mechanism underlying GLI-mediated transcription will further elucidate the contribution of the HH pathway to the initiation and progression of pancreatic cancer. Here, we present data supporting the physical and functional interaction between GLI1 and Suppressor of Fused (SUFU). Originally identified in Drosophila melanogaster as a component of the HH signaling, in mammals SUFU is a major regulator of GLI activity. In fact, SUFU has been shown to block HH signaling in cancer cells via cytoplasmic tethering of GLI1. Interestingly, using luciferase reporter assays we demonstrate that SUFU promotes rather than inhibit GLI activity in pancreatic cancer cells. SUFU binds to GLI1 and acts in synergy to activate HH target promoters, thus, suggesting that these molecules are at least part of the same nuclear complex. SUFU contains two GLI-interacting domains that bind and regulate GLI1 transcriptional activity independently. Interestingly, bioinformatics analysis reveals numerous proximal candidate sites for specific postranslational modifications suggesting a potential regulatory mechanism for these two independent motifs. Thus, these findings show that GLI-mediated activation of the HH target promoters requires intact nuclear SUFU activity and provides novel mechanistic information into the biology of the HH pathways in pancreatic carcinogenesis. M.E.F.-Z. is supported by the Mayo Clinic Cancer Center, NCI Grant CA125127, Mayo Clinic Pancreatic SPORE CA102701 and AACR-PanCAN Career Development Award for Pancreatic Cancer in honor of Carole and Bob Daly.