Fig. 2

In the absence of ligands, the SHH signaling pathway is inactive. When hedgehog ligands activate the SHH pathway, these hedgehog ligands bind to PTCH and relieve the repressive effects on SMO, a seven-transmembrane protein, resulting in the translocation of the full length activated forms of GLI (GLI^A) into the nucleus and activation of the expression of target genes, including PTCH and GLI themselves and many other cancer stemness-related genes. When the receptor activates the NOTCH pathway by binding with its ligand, the protein of the receptor is cleaved by a disintegrin and metalloproteinases (ADAMs) that mediate the cleavage of the NOTCH extracellular domain and γ-secretase, which mediates the cleavage of the NOTCH intracellular domain (NICD), which is then released. NICD is further translocated to the nucleus as a transcriptional effector and displaces the corepressor protein from CSL (CBF1, Suppressor of Hairless, LAG1)/RBPJ transcription factors, which leads to the activation of downstream signaling cascades to regulate target genes, including Hes1, Hey1, cyclinD1, c-myc, p21/Waf1 and nuclear factor-κB(NF- κB). WNT ligands are responsible for activating the WNT/β-catenin signaling pathway. In the absence of WNT ligands, β-catenin is phosphorylated by the destruction complex of β-catenin, which is a tertiary complex formed by the scaffolding proteins Axin and adenomatous polyposis coli (APC), the kinase proteins glycogen synthase kinase-3β (GSK-3β) and casein kinase 1α (Ck1α). This leads to β-catenin degradation via β-TrCP200 ubiquitination; therefore, β-catenin is failed to translocate from the cytoplasm to the nucleus. Contrastingly, in the presence of WNT ligands, the ligands bind to the FZD and the LRP receptor complex. Then the cytoplasmic domain of the LRP receptor is phosphorylated by GSK3β and CK1α, and the scaffolding protein Disheveled (Dvl) is recruited. The unphosphorylated β-catenin is released from the complex and enters the nucleus. In the cytoplasm, TAZ/YAP directly interacts with β-catenin and restricts its degradation. In the nucleus, β-catenin binds to TCF/LEF and enhances the recruitment of histone-modifying coactivators, such as BCL9, CBP/p300, and BRG1, to induce the transcription of WNT target genes. Many of these genes encode gene products capable of broadly upregulating cancer cell stemness, including CCND1, AXIN2, and the oncogene MYC