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

## TL;DR

This study identifies USP20 as a key gene in acute myeloid leukemia that promotes cancer progression by stabilizing CTNNB1, and shows that inhibiting USP20 can reduce leukemia growth.

## Contribution

The novel contribution is identifying USP20 as a super-enhancer-regulated oncogene in AML and demonstrating a new USP20 inhibitor with anti-leukemic effects.

## Key findings

- USP20 is frequently associated with super-enhancers and overexpressed in AML.
- Genetic or pharmacological inhibition of USP20 reduces AML cell survival and proliferation.
- USP20 stabilizes CTNNB1 via deubiquitination, and together they regulate AML target genes.

## Abstract

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 in vitro, while in vivo depletion of USP20 attenuated leukemia development and improved overall survival. AS1517499, a novel USP20 inhibitor identified via virtual screening, recapitulated these anti-leukemic effects in vitro and in vivo 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.