Hedgehog Signaling: Implications in Cancers and Viral Infections

Abstract

The hedgehog (SHH) signaling pathway is primarily involved in embryonic gut development, smooth muscle differentiation, cell proliferation, adult tissue homeostasis, tissue repair following injury, and tissue polarity during the development of vertebrate and invertebrate organisms. GLIoma-associated oncogene homolog (GLI) family of zinc-finger transcription factors and smoothened (SMO) are the signal transducers of the SHH pathway. Both SHH ligand-dependent and independent mechanisms activate GLI proteins. Various transcriptional mechanisms, posttranslational modifications (phosphorylation, ubiquitination, proteolytic processing, SUMOylation, and acetylation), and nuclear-cytoplasmic shuttling control the activity of SHH signaling pathway proteins. The dysregulated SHH pathway is associated with bone and soft tissue sarcomas, GLIomas, medulloblastomas, leukemias, and tumors of breast, lung, skin, prostate, brain, gastric, and pancreas. While extensively studied in development and sarcomas, GLI family proteins play an essential role in many host-pathogen interactions, including bacterial and viral infections and their associated cancers. Viruses hijack host GLI family transcription factors and their downstream signaling cascades to enhance the viral gene transcription required for replication and pathogenesis. In this review, we discuss a distinct role(s) of GLI proteins in the process of tumorigenesis and host-pathogen interactions in the context of viral infection-associated malignancies and cancers due to other causes. Here, we emphasize the potential of the Hedgehog (HH) pathway targeting as a potential anti-cancer therapeutic approach, which in the future could also be tested in infection-associated fatalities.

Keywords: GLI transcription factors; cancer; therapeutic; virus.

Figure 1

Schematic shows known full-length GLIoma-associated oncogene homolog (GLI) family functional domains at the transcriptional level. Similarities shared among all three types include Suppressor of fused (SUFU) binding sites, zinc finger DNA-binding domain, and activation domains. GLI1 has an additional SUFU binding site at the C-terminus, while GLI2/3 has repressor domains; additionally, GLI2 has an extra activation domain that supports its main feature of activating GLI-mediated transcription.

Figure 2

In the absence of Hedgehog (HH) ligand (SHH, IHH, and DHH), the Patched 1 (PTCH) transmembrane receptor at the base of the primary cilium maintains inhibition of Smoothened (SMO) G protein coupled receptor (GPCR) signaling. Upon HH binding, SMO inhibition is relieved and activates GLI transcription factors, usually sequestered by Suppressor of fused (SUFU), KIF7, and FUSED. GLIA refers to the transcriptionally active form of GLI. SMO is a popular drug target for cyclopamine, while GLI1 and GLI2-induced transcription can be inhibited by GANT61. It inhibits the HH signaling pathway downstream of SMO and SUFU, causing GLI1 nuclear accumulation. Target gene expression includes CYCLIN D1/2, CYCLIN E1, GLI1, N-MYC, Patched1, VEGF-C, and SNAIL to upregulate cell proliferation and tumor survival.

Figure 3

Schematic shows the role of GLI1 and GLI2 in cancer cell proliferation, migration, invasion, cell cycle regulation, angiogenesis, cell signaling, and survival kinases activation. Tumor suppressors downregulated by GLI are shown in red.

Figure 4

Schematic shows various stages and consequences of host-pathogen interactions. It also shows multiple signaling cascades, and transcription factors are demonstrated to be regulated by the HH pathway. Signaling molecules and transcription factors regulated by HH signaling could contribute to pathogen (virus or bacteria) entry, infection, pathogenesis (angiogenesis, fibrosis, inflammation), and activation of host foreign recognition network, host immune response, pathogen exit/elimination, and pathogen latency in the host.