Hedgehog signaling regulates the development and treatment of glioblastoma

Abstract

Glioblastoma (GBM) is the most common and fatal malignant tumor type of the central nervous system. GBM affects public health and it is important to identify biomarkers to improve diagnosis, reduce drug resistance and improve prognosis (e.g., personalized targeted therapies). Hedgehog (HH) signaling has an important role in embryonic development, tissue regeneration and stem cell renewal. A large amount of evidence indicates that both normative and non-normative HH signals have an important role in GBM. The present study reviewed the role of the HH signaling pathway in the occurrence and progression of GBM. Furthermore, the effectiveness of drugs that target different components of the HH pathway was also examined. The HH pathway has an important role in reversing drug resistance after GBM conventional treatment. The present review highlighted the relevance of HH signaling in GBM and outlined that this pathway has a key role in the occurrence, development and treatment of GBM.

Keywords: Hedgehog; Sonic; drug resistance; glioblastoma; patched-1; smoothened; therapeutics.

Figure 1.

Schematics of the mechanisms of HH signaling in GBM. (A) The HH protein activates a signaling cascade by binding to the 12-TM receptors PTCH1 and PTCH2 and leading to derepression of the seven-TM protein SMO. The HH signaling may now proceed downstream of SMO via a cytoplasmic protein complex consisting of Kif7, SUFU and GLIFL. When the signal reaches SUFU, the GLI1-SUFU complex dissociates, allowing it to release transcription factors (GLI1, GLI2 and GLI3). GLI2 and GLI3 are constitutively expressed and serve as transcriptional activators, GLIA, in their full-length form and as transcriptional repressors, GLIR, after partial proteasomal processing. Activation of SMO leads to the dephosphorylation of GLI2/3 P1-6 clusters and their dissociation from SUFU, which facilitates the transfer of GLIA into the nucleus and the initiation of transcription of target genes. (B) In the absence of the HH ligand, Ptch represses the activity of SMO by inhibiting its translocation into the PC. Gpr161 localizes to the PC to maintain high CAMP levels and PKA activity, which phosphorylates P1-6 clusters located on GLI2/3. Subsequently, GliFL is phosphorylated by PKA, GSK3 and CK1 and recognized by β-trCP. This results in the proteolytic cleavage of GliFL into the form of a C-terminal truncated repressor known as a GLiR. GLiR is translocated to the nucleus, where it binds to HH target gene promoters and inhibits their expression. HH, hedgehog; SMO, smoothened; PTCH, patched; TM, transmembrane; Kif7, kinesin family member protein 7; SUFU, suppressor of fused; GPR161, G-protein coupled receptor 61; CAMP, cyclic adenosine monophosphate; PKA, protein kinase A; GliFL, full-length glioma-associated oncogene; GSK3, glycogen synthase kinase-3; CK1, casein kinase 1; GLIR, GLI repressor; GLIA, GLI activator; PC, primary cilia.

Figure 2.

Related homolog genes (e.g. QKI), transcription factors (e.g. NANOG) and sialidase (e.g. NEU4) are able to activate the HH signaling pathway to maintain the self-renewal ability of GSCs by increasing SHH/GLI1 expression. ID1 and DLG5 inhibit cullin-3 ubiquitin ligase, activate HH signaling and promote GSC proliferation and tumorigenicity. DRP5 is specifically upregulated in the proneural subtype of GSC. NS activates the Wnt and HH signaling pathways by regulating the β/AKT axis of β-catenin and Gli1, respectively. Vascular endothelial cells in the tumor microenvironment may provide SHH to further activate HH signaling pathways, thereby promoting GSC properties. QKI, Quaking homolog; DRP5, dihydro pyrimidine-associated protein 5; SHH, Sonic Hedgehog; GBM, glioblastoma; SMO, smoothened; Gli, glioma-associated oncogene; GSC, glioblastoma stem cells; ID1, differentiation inhibitor 1; NS, microenvironmental nutritional stress; DLG5, discs large homolog 5.