The Role of Smoothened-Dependent and -Independent Hedgehog Signaling Pathway in Tumorigenesis

Abstract

The Hedgehog (Hh)-glioma-associated oncogene homolog (GLI) signaling pathway is highly conserved among mammals, with crucial roles in regulating embryonic development as well as in cancer initiation and progression. The GLI transcription factors (GLI1, GLI2, and GLI3) are effectors of the Hh pathway and are regulated via Smoothened (SMO)-dependent and SMO-independent mechanisms. The SMO-dependent route involves the common Hh-PTCH-SMO axis, and mutations or transcriptional and epigenetic dysregulation at these levels lead to the constitutive activation of GLI transcription factors. Conversely, the SMO-independent route involves the SMO bypass regulation of GLI transcription factors by external signaling pathways and their interacting proteins or by epigenetic and transcriptional regulation of GLI transcription factors expression. Both routes of GLI activation, when dysregulated, have been heavily implicated in tumorigenesis of many known cancers, making them important targets for cancer treatment. Hence, this review describes the various SMO-dependent and SMO-independent routes of GLI regulation in the tumorigenesis of multiple cancers in order to provide a holistic view of the paradigms of hedgehog signaling networks involving GLI regulation. An in-depth understanding of the complex interplay between GLI and various signaling elements could help inspire new therapeutic breakthroughs for the treatment of Hh-GLI-dependent cancers in the future. Lastly, we have presented an up-to-date summary of the latest findings concerning the use of Hh inhibitors in clinical developmental studies and discussed the challenges, perspectives, and possible directions regarding the use of SMO/GLI inhibitors in clinical settings.

Potential mechanisms of quercetin in cancer prevention: focus on cellular and molecular targets

“…The Discovery of PTCH1 gene mutation in people with Gorlin syndrome and sporadic forms of carcinoma basal cell carcinoma (CBC) has led to the importance of the hedgehog (HH) signalling pathway in human carcinogenesis [ 121 ]. Mutations in the PTCH1 gene or one of the components in the hedgehog (HH) signalling pathway is involved in the etiology and the development of some forms of cancers such as—medulloblastoma, breast cancer, colon cancer, pancreatic cancer, esophageal adenocarcinomas and in small cell lung cancer [ 122 ].…”

Bench to Bedside: New Therapeutic Approaches with Extracellular Vesicles and Engineered Biomaterials for Targeting Therapeutic Resistance of Cancer Stem Cells

“…The activity of Gli1 is regulated by Akt/p-S6K1 signaling. 78 ECM components laminin and fibronectin are also involved in the CSC self-renewal process. Chang et al demonstrated that laminin 511 helps maintain the breast cancer stemness properties by activating α6β1 integrin through the TAZdependent pathway.…”

“…Dysregulation of Shh upshoots Gli transcription factors, and its target gene BMI1 helps develop brain tumors. , Gli expression is regulated by several types of FAK/Ras signaling. The activity of Gli1 is regulated by Akt/p-S6K1 signaling . ECM components laminin and fibronectin are also involved in the CSC self-renewal process.…”

Quinolines and Oxazino-quinoline Derivatives as Small Molecule GLI1 Inhibitors Identified by Virtual Screening

“…Unfortunately, toxicity and poor drug likeness are two major limitations of currently available GLI1 inhibitors. 4,6,16 Recently, glabrescione B (GlaB, Table 1) 17 was used by us as the initial scaffold for the generation of a five-feature pharmacophoric model that led to the identification of negative modulators of GLI1 belonging to the classes of thiophene and pyrazolo-pyrimidine small molecules that populated databases of commercially available compounds. 18 In addition, the same pharmacophore allowed the prioritization of several 8-hydroxyquinoline derivatives as putative GLI1 binders that are described here.…”

“…Additional small molecules identified by virtual screening approaches were also described in recent years. Unfortunately, toxicity and poor drug likeness are two major limitations of currently available GLI1 inhibitors. ,, …”