Finally, the released GLI transcription factors translocate into the nucleus to execute transcriptional activation of specific target genes ( 15). The resultant signal leads to the component dissociation of a large protein complex comprising of Sufu and GLIs in the cytoplasm, releasing the GLI transcription factors. Upon SHh binding to PTCH, the inhibitory interaction is terminated through internalization of PTCH, releasing SMO and allowing for phosphorylation to transduce signal into the cytoplasm ( 14). In the absence of SHh, PTCH-1 and, redundantly, PTCH-2, catalytically inhibit downstream signaling activity with seven-transmembrane G-protein-coupled receptor, Smoothened (SMO) ( 11– 13). SHh-mediated transduction is initiated via extracellular SHh ligand binding to the 12-span transmembrane receptor, PATCHED-1 (PTCH-1) or the redundant receptor PTCH-2, in target cells ( 9, 10). Herein, we focus specifically on our current understanding of SHh-GLI pathway and its clinical significance in human development and the consequences of its dysregulation in disease progression ( 5– 8). Due to its conserved nature, and apparent critical functionality across organisms, SHh and the downstream pathway members have evolved to serve vastly diverse roles in both embryonic and non-embryonic cellular homeostasis. SHh plays a critical role in the embryonic development that is necessary for certain cell differentiation and maintenance of tissue polarity ( 4). SHh, first discovered in Drosophila, has been found to be highly conserved across many different vertebrate species including human, mouse, rat, frog, fish, and chicken, and is the most studied member of the hedgehog family ( 3). IHh and DHh are reported to be involved in normal tissue development, such as bone formation ( 2). The Hh family of proteins contains three subfamilies: sonic hedgehog (SHh), desert hedgehog (DHh) and Indian hedgehog (IHh) ( 1). GLI1 is an effector transcriptional factor distal to both the canonical and non-canonical Hedgehog (Hh) signaling pathways.
Therefore, understanding the underlying mechanisms driving GLI1 dysregulation can provide prognostic and diagnostic biomarkers to identify a patient population that would derive therapeutic benefit from either direct inhibition of GLI1 or targeted therapy towards proteins downstream of GLI1 regulation. The consequences of GLI1 oncogenic activity, specifically the activity surrounding DNA damage repair proteins, such as NBS1, and cell cycle proteins, such as CDK1, can be linked to tumorigenesis and chemoresistance. All of these are driven, in part, by GLI1’s role in regulating cell cycle, DNA replication and DNA damage repair processes. GLI1 has low-level expression in differentiated tissues, however, in certain cancers, aberrant activation of GLI1 has been linked to the promotion of numerous hallmarks of cancer, such as proliferation, survival, angiogenesis, metastasis, metabolic rewiring, and chemotherapeutic resistance. GLI1 is a transcriptional effector at the terminal end of the Hedgehog signaling (Hh) pathway and is tightly regulated during embryonic development and tissue patterning/differentiation. 2Department of Medicine, Stony Brook University, Stony Brook, NY, United States.1Oncology Department, Drug Discovery Division, Southern Research, Birmingham, AL, United States.
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