Targeting GLI Transcription Factors in Cancer

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.

Keywords: GLI inhibitors; cancer; cancer stem cells; glioma-associated oncogene homolog; hedgehog signaling.

Figure 1

Mechanism of Hedgehog pathway activation. In the absence of the Hh ligand (left panel), PTCH1, which is found in the primary cilium, binds to SMO and prevents its transclocation into the cilium. This leads to the sequestration of GLIs in the cytoplasm, their association with the negative regulator SUFU, phosphorylation by GSK3β/PKA/CK1 kinases, and subsequent cleavage into repressor forms (GLI^R). In the presence of the Hh ligand (right panel), SMO inhibition by PTCH1 is relieved, and SMO translocates to the primary cilium and prevents GLI2 and GLI3 cleavage. GLI proteins dissociate from SUFU, are phosphorylated by PKC, and converted into their active forms (GLI^A), which then translocate to the nucleus and induce target genes expression. (Hh; hedgehog, PTCH1; Patched 1, SMO; Smoothened, GLI; gliomaassociated oncogene, GSK3β; glycogen synthase kinase 3β; PKA; protein kinase A, CK1; casein kinase 1, SUFU; Supressor of Fused, PKC; protein kinase C).

Figure 2

Crosstalk of the Hedgehog pathway with other protumorigenic pathways. GLI proteins may be activated through canonical (SMO-dependent) or non-canonical (SMO-independent) mechanisms. Multiple cancer-related signaling pathways may converge on and regulate GLIs, which represent molecular hubs governing various pro-tumorigenic processes such as proliferation, cell survival, epithelial-to-mesenchymal transition (EMT), genetic instability, stem cell self-renewal, and angiogenesis. Different possibilities to block GLIs are illustrated.