USP20, a Super-enhancer Regulated Gene, Promotes Acute Myeloid Leukemia Progression through CTNNB1 Deubiquitination
Jia Cheng, Fang Fang, Zhiheng Li, Jianwei Wang, Linbo Cai, Ling Xu, Yanfang Tao, Juanjuan Yu, Gen Li, Zimu Zhang, Zexi Cui, Yang Yang, Tiandan Li, Di Wu, Xiaolu Li, Yifang Ding, Zong Zhai, Mengmeng Gu, Xue Li, Xingxing Wu, Pengju Yang, Chunxia Shi, Huike Bai, Xiaodong Wang
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.
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…
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Taxonomy
TopicsAcute Myeloid Leukemia Research · Ubiquitin and proteasome pathways · Blood disorders and treatments