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Last update 08 May 2025

USP47

Last update 08 May 2025

Basic Info

Synonyms

Deubiquitinating enzyme 47, Ubiquitin carboxyl-terminal hydrolase 47, ubiquitin specific peptidase 47

+ [3]

Introduction

Ubiquitin-specific protease that specifically deubiquitinates monoubiquitinated DNA polymerase beta (POLB), stabilizing POLB thereby playing a role in base-excision repair (BER). Acts as a regulator of cell growth and genome integrity. May also indirectly regulate CDC25A expression at a transcriptional level.

Drugs associated with USP47

P22077

Target

USP47 x USP7

Mechanism

USP47 inhibitors [+1]

Active Org.

Progenra, Inc. [+1]

Originator Org.

Progenra, Inc.

Active Indication

Pulmonary Disease, Chronic Obstructive [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with USP47

100 Translational Medicine associated with USP47

0 Patents (Medical) associated with USP47

Literatures (Medical) associated with USP47

01 May 2025·Pharmacological Research

Targeting USP47 enhances the efficacy of KRAS inhibitor in KRASG12C mutated non-small cell lung cancer by controlling deubiquitination of c-Myc

Article

Author: Hwang, Inah ; Song, Eun Joo ; Choo, Hyunah ; Kim, Jinhyeok ; Hwang, SuA ; Shin, Hyungkyung ; Kim, Eunice EunKyeong ; Oh, Yeonji ; Jeong, Jeong Hyun ; Shin, Sang Chul

FDA-approved KRAS^G12C inhibitors, like Sotorasib, target G12C-mutated KRAS in NSCLC. However, issues with insensitivity and drug resistance have emerged, requiring the development of new combination therapies to overcome these limitations. USP47 has been identified as a regulator of cancer-related signaling pathways such as Wnt, Hippo, and p53. However, its role in the KRAS signaling pathway remains largely unexplored and USP47 inhibitors are less developed than those targeting its homolog, USP7. Here, we identify USP47 as a novel therapeutic target in KRAS^G12C-mutated NSCLC and report K-552, a selective USP47 inhibitor, as a potential treatment strategy. We demonstrate that USP47 stabilizes c-Myc by preventing its proteasomal degradation through deubiquitination, thereby promoting NSCLC cell proliferation. Additionally, the compound K-552, a USP47 inhibitor identified through virtual screening, effectively destabilizes c-Myc and inhibits KRAS^G12C-mutated NSCLC cell proliferation. Furthermore, USP47 inhibition-either by siRNA knockdown or K-552 treatment-enhances the efficacy of Sotorasib in vitro and in vivo. Together, our findings establish USP47 as a promising therapeutic target in KRAS^G12C-mutated NSCLC and introduce K-552 as a USP47 inhibitor with potential for combination therapy with KRAS^G12C inhibitors.

15 Apr 2025·Journal of Clinical Investigation

An inherited predisposition allele promotes gastric cancer via enhancing deubiquitination-mediated activation of epithelial-to-mesenchymal transition signaling

Article

Author: Xu, Wenjie ; Chen, Fei Xavier ; Chen, Zhaolin ; Tao, Bolin ; Liu, Jiaxian ; Zhang, Ping ; Sun, Menghong ; Wang, Yanong ; Wang, Jianan ; Wang, Xuanyi ; Wang, Mengyun ; Song, Aixia ; Zhang, Qin ; Wang, Zixian ; Xu, Tao ; Wei, Gong-Hong ; Wang, Zhenning

Genome-wide human genetic studies have identified inherited cis-regulatory loci variants that predispose to cancers. However, the mechanisms by which these germline variants influence cancer progression, particularly through gene expression and proteostasis control, remain unclear. By analyzing genomic data from a gastric cancer (GC) case-control study (2,117 individuals), focusing on the ubiquitin-specific protease (USP) family, we identify the SNP rs72856331 (G>A) in the promoter region of the proto-oncogene USP47 as a putative susceptibility allele for GC. Mechanistically, the risk allele G is associated with enhanced USP47 expression, mediated by altered recruitment of the transcription factor GLI3 and changes in the epigenetic status at promoter. CRISPR/Cas9-mediated single-nucleotide conversion into risk allele G results in increased GLI3 binding and subsequent USP47 upregulation. The depletion of GLI3 results in a reduction of cancer-related phenotypes, similar to those observed following USP47 knockdown. Furthermore, we identify Snai1 as a deubiquitination target of USP47, explaining USP47-dependent activation of the epithelial-mesenchymal transition pathway and tumor progression. Our findings identify an important genetic predisposition that implicates the perturbation of transcription and proteostasis programs in GC, offering insights into prevention and therapeutic strategies for genetically stratified patients.

04 Sep 2024·Molecular Cancer Research

USP44 Overexpression Drives a MYC-Like Gene Expression Program in Neuroblastoma through Epigenetic Reprogramming

Article

Author: Johnsen, Steven A. ; Paolini, Lucia ; Ekstrom, Thomas L. ; Hussain, Sajjad ; Bedekovics, Tibor ; Ali, Asma ; Koster, Jan ; Galardy, Paul J. ; Mahmood, Hina ; Rosok, Raya M.

AbstractNeuroblastoma is an embryonic cancer that contributes disproportionately to death in young children. Sequencing data have uncovered few recurrently mutated genes in this cancer, although epigenetic pathways have been implicated in disease pathogenesis. We used an expression-based computational screen that examined the impact of deubiquitinating enzymes on patient survival to identify potential new targets. We identified the histone H2B deubiquitinating enzyme USP44 as the enzyme with the greatest impact on survival in patients with neuroblastoma. High levels of USP44 significantly correlate with metastatic disease, unfavorable histology, advanced patient age, and MYCN amplification. The subset of patients with tumors expressing high levels of USP44 had significantly worse survival, including those with tumors lacking MYCN amplification. We showed experimentally that USP44 regulates neuroblastoma cell proliferation, migration, invasion, and neuronal development. Depletion of the histone H2B ubiquitin ligase subunit RNF20 resulted in similar findings, strongly implicating this histone mark as the target of USP44 activity in this disease. Integration of transcriptome and epigenome in analyses demonstrates a distinct set of genes that are regulated by USP44, including those in Hallmark MYC target genes in both murine embryonic fibroblasts and the SH-SY5Y neuroblastoma cell line. We conclude that USP44 is a novel epigenetic regulator that promotes aggressive features and may be a novel target in neuroblastoma.Implications: This study identifies a new genetic marker of aggressive neuroblastoma and identifies the mechanisms by which its overactivity contributes to the pathophysiology of this disease.

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