GSK3ß and Gli3 play a role in activation of Hedgehog-Gli pathway in human colon cancer - Targeting GSK3ß downregulates the signaling pathway and reduces cell proliferation.

Biochimica et biophysica acta

PubMedID: 26385428

Trnski D, Sabol M, Gojevic A, Martinic M, Ozretic P, Musani V, Ramic S, Levanat S. GSK3ß and Gli3 play a role in activation of Hedgehog-Gli pathway in human colon cancer - Targeting GSK3ß downregulates the signaling pathway and reduces cell proliferation. Biochim Biophys Acta. 2015;1852(12):2574-2584.
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 GSK3ß. Our clinical data reveals high expression levels of GSK3ß and Gli3 in human colon cancer tissue samples, with positive correlation between GSK3ß expression and DUKES' stage. Further experiments on colon cancer cell lines have shown that a deregulated GSK3ß upregulates Hh-Gli signaling and positively affects colon cancer cell survival. We show that inhibition of GSK3ß 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-GSK3ß 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 GSK3ß. Gli3 seems to be the main pathway effector, highlighting the activator potential of this transcription factor, which is highly dependent on GSK3ß function and fine tuning of the Gli3-SuFu-GSK3ß platform.