Abstract
The glioma-associated oncogene (GLI) family consists of GLI1, GLI2, and GLI3 in mammals. This family has important roles in development and homeostasis. To achieve these roles, the GLI family has widespread outputs. GLI activity is therefore strictly regulated at multiple levels, including via post-translational modifications for context-dependent GLI target gene expression. The protein arginine methyl transferase (PRMT) family is also associated with embryogenesis, homeostasis, and cancer mainly via epigenetic modifications. In the PRMT family, PRMT1, PRMT5, and PRMT7 reportedly regulate GLI1 and GLI2 activity. PRMT1 methylates GLI1 to upregulate its activity and target gene expression. Cytoplasmic PRMT5 methylates GLI1 and promotes GLI1 protein stabilization. Conversely, nucleic PRMT5 interacts with MENIN to suppress growth arrest-specific protein 1 expression, which assists Hedgehog ligand binding to Patched, indirectly resulting in downregulated GLI1 activity. PRMT7-mediated GLI2 methylation upregulates its activity through the dissociation of GLI2 and Suppressor of Fused. Together, PRMT1, PRMT5, and PRMT7 regulate GLI activity at multiple revels. Furthermore, the GLI and PRMT families have strong links with various cancers through cancer stem cell maintenance. Therefore, PRMT-mediated regulation of GLI activity would have important roles in cancer stem cell maintenance.
Highlights
The Hedgehog (HH) signaling pathway is one of the most important pathways in tissue development and homeostasis [1,2]
After one of the three HH ligands binds to PTCH (Figure 1B), with assistance from the cell-surface proteins cell adhesion molecule-related/downregulated by oncogenes (CDO), brother of CDO (BOC), or growth-arrest-specific 1 (GAS1) [14], SMO accumulates in primary cilia and is fully activated
PRMT1 upregulates GLI1 transcriptional activity via the methylation of an arginine residue at 597 in GLI1. This strongly induces the expression of some GLI1 target genes, such as insulin growth factor-binding protein 6 (IGFBP6) and B-cell lymphoma 2 (BCL2), that are involved in Pancreatic ductal adenocarcinoma (PDAC) cell survival [60]
Summary
The Hedgehog (HH) signaling pathway is one of the most important pathways in tissue development and homeostasis [1,2]. Among the GLI family of proteins, GLI2 is the major activator of HH signaling, whereas GLI3 is the major repressor. The HH signaling pathway has a variety of outputs in embryogenesis, homeostasis, and cancers, and the GLI family is a key player that exhibits widespread outputs. The protein arginine methyl transferase (PRMT) family is involved in embryogenesis and homeostasis through regulation of gene transcription, mRNA splicing, and stem cell function [8]. PRMTs are involved in cancer development through oncogenic signal transduction, epithelial-mesenchymal transition (EMT), and CSC maintenance [10]. The GLI family and PRMT family regulate normal and CSC function, which act as the origin of tissue and cancer development. Recent reports revealed PRMT1, PRMT5, and PRMT7 regulate GLI1 and GLI2 activity in normal and cancer cells. We discuss the roles of PRMT-mediated GLI regulation in relation to mainly CSC maintenance
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