USP20, a Super-enhancer Regulated Gene, Promotes Acute Myeloid Leukemia Progression through CTNNB1 Deubiquitination

Acute Myeloid Leukemia (AML) is a heterogeneous hematologic malignancy driven by genetic and epigenetic alterations, where super-enhancers (SEs) play key oncogenic roles, representing promising therapeutic targets in AML. Through H3K27ac ChIP-seq profiling of 7 AML cell lines and 13 primary samples, we identified USP20 as the deubiquitinase that most frequently associated with super-enhancers. Public database analysis confirmed USP20 overexpression in AML and its correlation with adverse prognosis. Genetic knockdown of USP20 via shRNA significantly induced apoptosis and suppressed proliferation in AML cells <i>in vitro</i>, while <i>in vivo</i> depletion of USP20 attenuated leukemia development and improved overall survival. AS1517499, a novel USP20 inhibitor identified via virtual screening, recapitulated these anti-leukemic effects <i>in vitro</i> and <i>in vivo</i> with low toxicity. Mechanistically, USP20 interacts with CTNNB1 and stabilizes the CTNNB1 protein via deubiquitination. Cut&tag analysis indicated that USP20 co-localizes with CTNNB1 on the genome, where they jointly regulate target genes in AML. Collectively, our study identified USP20 as a super-enhancer-regulated oncogene maintaining AML cell survival and proliferation through CTNNB1 stabilization. Pharmacologic targeting of USP20 with AS1517499 presents a promising therapeutic strategy targeting the SE-USP20- CTNNB1 axis.