Abstract
Aberrant activation of hedgehog (Hh) signaling has been observed in a wide variety of tumors and accounts for more than 25% of human cancer deaths. Inhibitors targeting the Hh signal transducer Smoothened (SMO) are widely used and display a good initial efficacy in patients suffering from basal cell carcinoma (BCC); however, a large number of patients relapse. Though SMO mutations may explain acquired therapy resistance, a growing body of evidence suggests that the non-canonical, SMO-independent activation of the Hh pathway in BCC patients can also account for this adverse effect. In this review, we highlight the importance of glioma-associated oncogene (GLI) transcription factors (the main downstream effectors of the canonical and the non-canonical Hh cascade) and their putative role in the regulation of multiple oncogenic signaling pathways. Moreover, we discuss the contribution of the Hh signaling to malignant transformation and propose GLIs as central hubs in tumor signaling networks and thus attractive molecular targets in anti-cancer therapies.
Highlights
The canonical pathway of the Hh signaling is initiated by the release of Hh ligands, namely Sonic Hh (SHH), Desert Hh (DHH), and Indian HH (IHH) [1]
Binding of the Hh ligand to the receptor leads to the accumulation of SMO and translocation of glioma-associated oncogene (GLI) transcription factors in a microtubule-based protrusion of the cell membrane–primary cilium [2,3,4]
GLIs dissociate from the negative regulator Suppressor of Fused (SUFU), are converted into their activator forms (GLIA ) and translocate to the nucleus (Figure 1)
Summary
Hedgehog (Hh) signaling plays a key role during embryonic development and tissue patterning. Binding of the Hh ligand to the receptor leads to the accumulation of SMO and translocation of glioma-associated oncogene (GLI) transcription factors in a microtubule-based protrusion of the cell membrane–primary cilium [2,3,4]. In the absence of ligand, SUFU directly binds GLI proteins and retains them in the cytoplasm, facilitating their processing into a repressor form (GLIR ). Both GLI2 and GLI3 are subject to a limited proteolysis, giving rise to truncated repressor forms (GLI2R and GLI3R ). The repressor form translocates to the nucleus, where it competes with the activator form for the with the activator formthus for the DNA-binding gene hampering.
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