Fine-Tuning of GLI Activity through Arginine Methylation: Its Mechanisms and Function

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.

Research progress on PRMTs involved in epigenetic modification and tumour signalling pathway regulation (Review)

“…PRMT3 methylates hypoxia-inducible factor (HIF)1α at R282 and stabilizes the structure of HIF1α, while activating the HIF1/VEGFA signalling pathway to promote tumorigenesis (88). PRMT1, -5 and -7 regulate glioma-associated oncogene 1 (GLI1) and GLI2 activity (89). Methylation of GLI1 by PRMT1 upregulates its activity and promotes target gene expression.…”

The Role of PRMT5 in Immuno-Oncology

“…Next, type I PRMTs modify asymmetrical methylated arginine and type II PRMTs modify symmetrically methylated arginine, while type III PRMT (PRMT7) modifies only monomethyl arginine. This figure was illustrated using Adobe Illustrator 2022 and was modified from our previous work [ 31 ].…”

Beyond controlling cell size: functional analyses of S6K in tumorigenesis

“…In addition to charging cell size, metabolic homeostasis, and apoptosis to contribute to cell malignancies, S6K also tethers other signaling pathways to control cell proliferation and migration. For instance, S6K1 directly phosphorylates glioma-associated oncogenes (Gli1), a key effector of the Hedgehog signaling pathway [ 185 ], and unleashes Gli1 from its endogenous inhibitor SuFu to enhance its transcriptional activity and tumorigenesis capability [ 186 ]. Similarly, Gli2 also goes through S6K1-mediated phosphorylation and disassociation from SuFu, contributing to chondrocyte proliferation and differentiation [ 187 ].…”