Dr. Anthony E. Oro and colleagues (Stanford University) have identified two key Gli protein degradation signals that directly affect tumor latency in a mouse model of human skin cancer. Their paper has been made available online ahead of print and will appear on the cover of the February 1 issue of the scientific journal Genes & Development. Gli proteins are transcriptional mediators of the Sonic Hedgehog intracellular signaling pathway. Aberrant Shh signaling is implicated in a variety of human birth defects and about 25% of human tumors. Dr. Oro and colleagues found two sequences in the Gli1 protein – called Dn and Dc – that are recognized by the proteasome and facilitate Gli protein destruction. Mutations in these sequences (or “degrons” as they are called) prevent Gli1 degradation, causing, rather, the Gli1 protein to accumulate, and lead to accelerated tumorigenesis. “Although we knew inducing hedgehog signaling in cells played an important role in human cancer induction and maintenance, we were puzzled by why it took so long in many cases. We were excited to find that normal cells have a way of protecting themselves from too much of the active Gli protein and surprised to discover that cancer cells appear to have disarmed that ability.” Dr. Oro and colleagues used transgenic mice expressing various forms of the Gli1 protein to demonstrate the link between Gli1 accumulation and tumor latency. Transgenic mice expressing wild-type Gli1 (in which the degrons are completely intact) develop basal cell carcinoma (BCC)-like tumor 6-8 weeks after birth. Mice expressing an altered form of either Dn or Dc (in which Gli1 is partially stabilized) develop BCC-like lesions at an earlier age. Remarkably, mice with mutated forms of both degrons (in which Gli1 is not degraded by the proteasome) die at birth, presenting severe ulcerating skin lesions similar to human BCCs. This work convincingly shows that Gli protein accumulation contributes to the latency of Shh-dependent tumor formation, and that the modulation of Gli protein stability may thus represent a novel anticancer therapy. “We hope our studies will lead to ways to enhance the cell’s ability to get rid of Gli and halt cancer development,” adds Dr. Oro.
