Hedgehog signaling pathway: Epigenetic regulation and role in disease and cancer development

Abstract

The evolutionarily conserved Hedgehog (Hh) signaling pathway have critical roles in development and homeostasis of tissues. Under physiological conditions, Hh is controlled at different levels via stem cell maintenance and tissue regeneration. Aberrant activation of this signaling pathway may occur in a wide range of human diseases including different types of cancer. In this review we present a concise overview on the key genes composing Hh signaling pathway and provide recent advances on the molecular mechanisms that regulate Hh signaling pathway from extracellular and receptors to the cytoplasmic and nuclear machinery with a highlight on the role of microRNAs. Furthermore, we focus on critical studies demonstrating dysregulation of the Hh pathway in human disease development, and potential therapeutic implications. Finally, we introduce recent therapeutic drugs acting as Shh signaling pathway inhibitors, including those in clinical trials and preclinical studies.

An Unbalanced Chromosome Translocation Between 7p22 and 12q13 Leads to ACTB-GLI1 Fusion in Pericytoma

“…The members of the GLI family are main mediators of the highly conserved Hedgehog signaling pathway, which plays a critical role in embryonic development (17)(18)(19)(20). Aberrant Hedgehog signaling is associated with the development and progression of various types of cancer and is implicated in multiple aspects of tumorigenesis (21)(22)(23)(24)(25)(26)(27). Transcript variant 2 (NM_001160045) lacks the first two coding exons of transcript variant 1, transcription initiation occurs from an internal AUG site, and codes for Nterminally truncated protein isoform 2 (NP_001153517), also known as GLI1DeltaN (32).…”

Sonic Hedgehog Signaling Pathway in Endothelial Progenitor Cell Biology for Vascular Medicine

“…SHh signaling pathway regulation by EV-derived miRNA is divided in to three level of activation; in the first level, miRNA binds with membrane surface receptors or proteins (PTCH1 or activates Rho GTPase) and second level, with cytoplasmic proteins Gli1,2,3 and final, nuclear level of activating estimates as the strongest activation of SHh among three level[34][35][36] (Figure 2). The clinical study showed that osteoarthritis patient's chondrocytes were highly expressed on SHh, PTCH1, Gli1, and MMP-13, and positively correlated with overexpression of miRNA-602 and miRNA-608 which may activate all three level[37].…”

MiR-132/212 promotes the growth of precartilaginous stem cells (PCSCs) by regulating Ihh/PTHrP signaling pathway

“…The Hedgehog (Hh) signaling pathway is evolutionarily conserved and plays important roles in homeostasis and development. Deregulation of Hh signaling results in a wide range of human diseases [19]. Particularly, accumulating evidence indicates the critical role of Hh signaling in bone development, homeostasis and repair, such as limb patterning, endochondral ossification and joint formation [20,21].…”