Ubiquitin-specific protease 21 (USP21)

Ubiquitin-specific protease 21 (USP21) is a member of the ubiquitin-specific protease family of deubiquitinases (DUBs), which cleave ubiquitin from various substrate proteins to regulate their stability, localization, and activity[1][2][3]. USP21 modulates a range of cellular functions, including DNA repair (by stabilizing BRCA2 and promoting homologous recombination), transcriptional activation (via deubiquitination of histone H2A and transcription factors like GATA3), regulation of immune responses, and maintenance of mitochondrial function[1][2][3][5]. USP21 is overexpressed in several cancers, where it drives tumorigenesis, metastasis, and stemness by stabilizing oncogenic proteins such as ZEB1, AURKA, FOXM1, and others[7]. Genetic or pharmacological inhibition of USP21 disrupts energy metabolism and cell proliferation in cancer cells, highlighting its promise as a therapeutic target[3][4][7]. Safety considerations include potential effects on genome stability and redundancy with other deubiquitinases; no clinically approved inhibitors exist as of 2024[4].

Other names

USP23ubiquitin specific peptidase 21ubiquitin-specific processing protease 21

Inhibition of USP21 prevents deubiquitination of target proteins, leading to their degradation or functional inactivation[4] Inhibition disrupts stabilization of proteins such as BRCA2, ZEB1, AURKA, FOXD1, FOXM1, and EZH2 involved in tumorigenesis and cell proliferation[5][7]