Abstract
The hedgehog (HH) signaling pathway regulates normal cell growth and differentiation. As a consequence of improper control, aberrant HH signaling results in tumorigenesis and supports aggressive phenotypes of human cancers, such as neoplastic transformation, tumor progression, metastasis, and drug resistance. Canonical activation of HH signaling occurs through binding of HH ligands to the transmembrane receptor Patched 1 (PTCH1), which derepresses the transmembrane G protein-coupled receptor Smoothened (SMO). Consequently, the glioma-associated oncogene homolog 1 (GLI1) zinc-finger transcription factors, the terminal effectors of the HH pathway, are released from suppressor of fused (SUFU)-mediated cytoplasmic sequestration, permitting nuclear translocation and activation of target genes. Aberrant activation of this pathway has been implicated in several cancer types, including medulloblastoma, rhabdomyosarcoma, basal cell carcinoma, glioblastoma, and cancers of lung, colon, stomach, pancreas, ovarian, and breast. Therefore, several components of the HH pathway are under investigation for targeted cancer therapy, particularly GLI1 and SMO. GLI1 transcripts are reported to undergo alternative splicing to produce truncated variants: loss-of-function GLI1ΔN and gain-of-function truncated GLI1 (tGLI1). This review covers the biochemical steps necessary for propagation of the HH activating signal and the involvement of aberrant HH signaling in human cancers, with a highlight on the tumor-specific gain-of-function tGLI1 isoform.
Highlights
The hedgehog (HH) gene was first discovered by Christiane Nusslein-Volhard and Eric F.Weischaus in 1980 through a screen for embryonic lethal mutants of Drosophila melanogaster that disrupted the larval body plan [1]
Aberrant pathway activation has been linked to the development of several cancer types with three distinct mechanisms proposed: ligand-independent signaling resulting from protein mutations as in the cases of basal cell carcinoma (BCC), medulloblastoma, and rhabdomyosarcoma by way of Patched 1 (PTCH1) mutations (Type I); ligand-dependent autocrine or juxtacrine signaling via overexpression of the Sonic hedgehog (SHH) ligand observed in colorectal, ovarian, and pancreatic cancers (Type II); and ligand-dependent paracrine signaling via SHH ligand overexpression induced by tumor–stroma interactions commonly found in colon, pancreatic, and prostate cancers (Type III) [4,17,18]
Using a GBM xenograft mouse model, we showed that truncated GLI1 (tGLI1)-expressing tumor cells were significantly more infiltrative than glioma-associated oncogene homolog 1 (GLI1)-expressing cells promoting the aggressiveness of GBM [24]. tGLI1 gains the ability to promote the aggressiveness of GBM as a novel mediator of angiogenesis through regulation of VEGFR2 and vascular endothelial growth factor (VEGF)-A in an autocrine loop
Summary
The hedgehog (HH) gene was first discovered by Christiane Nusslein-Volhard and Eric F. Named for the short, “spiked” phenotype of the cuticle of the mutant Drosophila larvae, HH signaling is evolutionarily conserved from flies to humans and has been deemed a key regulator of several fundamental processes in vertebrate embryonic development including cell fate, patterning, proliferation, survival, and differentiation [2,3]. GLI proteins are marked for processing, e.g., through sequestration in the cytoplasm by SUFU. A protein complex containing KIF7 and SUFU bound to GLI transcription to the primary cilium. A protein complex containing KIF7 and SUFU bound to GLI transcription factors factors is dynamically trafficked to the activated SMO. Active SMO promotes release of GLI proteins from from SUFU, resulting in nuclear accumulation of GLI1/2 and activation of target genes. SUFU, resulting in nuclear accumulation of GLI1/2 and activation of target genes
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