USP10 promotes glioma stem cell maintenance and glioblastoma growth by antagonizing DTX3L-mediated SATB2 ubiquitination

Special AT-rich sequence-binding protein 2 (SATB2) is a nuclear matrix-associated protein with a pivotal role in glioblastoma (GBM) progression. However, the mechanisms underpinning aberrant SATB2 expression remain elusive. Here, we identify the ubiquitin specific peptidase 10 (USP10) as a deubiquitinase and the deltex E3 ubiquitin ligase 3 L (DTX3L) as a ubiquitin ligase of SATB2 in glioma stem cells (GSCs). USP10 and DTX3L regulate SATB2 ubiquitination at the K266 residue through mutually exclusive interactions and opposing activities. USP10, enriched in GSCs, is induced by transcription factor YY2. Knockdown of USP10 or overexpression of DTX3L markedly downregulates SATB2, resulting in the inhibition of GSC self-renewal and GBM growth, which can be rescued by the overexpression of SATB2. Importantly, pharmacological inhibition of USP10 by Wu-5 effectively suppresses tumor growth. These findings highlight the antagonistic roles of USP10 and DTX3L in the regulation of GBM malignancy and propose USP10 as a potential therapeutic target. Dysregulation in proteolysis contributes to brain tumorigenesis. Here the authors report that USP10 deubiquitinase is enriched in glioma stem cells (GSCs), which antagonizes DTX3L-mediated ubiquitination of SATB2, a major driver of GSC proliferation and self-renewal.