Hu Y, Jiang Y, Zhang Z, Wang J, Zhang B, Gong L, Ji L, Pu Z, Yang X, Zou J, Yin Y

Previous studies have demonstrated that glucocorticoid receptor ? (GR?) functions as an oncoprotein, regulating the malignant phenotypes and stem-like cell maintaining in human glioblastoma (GBM). Of the glucocorticoid receptor (GR) isoforms, GR? and GR? are highly homologous, though the mechanism underlying the distinct functions of these two isoforms in GBM ...

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has not been clarified. Here by establishing a carboxyl-terminal (COOH-terminal) deletion mutant, we determined that GR? can be ubiquitinated. We also found that its COOH terminal is essential for this ubiquitination. The mutation of a lysine to arginine at residue 733 (K733R) blocked the ubiquitination of GR?, indicating that K733 is a key site for ubiquitination. Using K733R to establish nonubiquitinated GR?, we demonstrated that ubiquitination not only regulates the stability and nuclear translocation of GR?, but is also a vital mechanism for its oncogenic functions in vitro and in vivo. Protein interaction assay further indicated that ubiquitin-specific protease 49 (USP49) is a GR?-binding protein and the interaction depends on GR? ubiquitination. USP49 knockdown resulted in a decrease of cell proliferation, invasion, and an increase of cell apoptosis. More importantly, USP49 knockdown increased ubiquitination and amplified the oncogenic effects of GR?, confirming the decisive role of ubiquitination on GR? carcinogenicity. Taken together, these findings established that ubiquitination is a vial process for GR? the execution of oncogenic functions in GBM and that the K733 site is crucial for ubiquitination of GR?. IMPLICATIONS: This work is the first identify of the activation GR? by a single lysine point-mediated ubiquitination and proteasome degradation, which determines its oncogenic functions in GBM.

Date: Dec. 01, 2021

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