GSK3β and Gli3 play a role in activation of Hedgehog-Gli pathway in human colon cancer - Targeting GSK3β downregulates the signaling pathway and reduces cell proliferation

The role of Hedgehog-Gli (Hh-Gli) signaling in colon cancer tumorigenesis has not yet been completely elucidated. Here we provide strong evidence of Hh-Gli signaling involvement in survival of colon cancer cells, with the main trigger of activation being deregulated GSK3 beta. Our clinical data reveals high expression levels of GSK3 beta and Gli3 in human colon cancer tissue samples, with positive correlation between GSK3 beta expression and DUKES' stage. Further experiments on colon cancer cell lines have shown that a deregulated GSK3 beta upregulates Hh-Gli signaling and positively affects colon cancer cell survival. We show that inhibition of GSK3 beta with lithium chloride enhances Gli3 processing into its repressor form, consequently downregulating Hh-Gli signaling, reducing cell proliferation and inducing cell death. Analysis of the molecular mechanisms revealed that lithium chloride enhances Gli3-SuFu-GSK3 beta complex formation leading to more efficient Gli3 cleavage and Hh-Gli signaling downregulation. This work proposes that activation of the Hh-Gli signaling pathway in colon cancer cells occurs non-canonically via deregulated GSK3 beta. Gli3 seems to be the main pathway effector, highlighting the activator potential of this transcription factor, which is highly dependent on GSK3 beta function and fine tuning of the Gli3-SuFu-GSK3 beta platform. (C) 2015 Elsevier B.V. All rights reserved.