Caspase 3-Specific Cleavage of Ubiquitin-Specific Peptidase 48 Enhances Drug-Induced Apoptosis in AML

Authors

Zhanglin Zhang
Xiang Lin
Yaling Yang
Xuemei Wang
Yi Wang
Xianbao Huang
Miao Hong
Wei Gao
Hua He
M James You
Yi Yang
Guangyao Kong

Publication Date

12-1-2025

Journal

Cancer Biology & Therapy

Abstract

Dysfunction or dysregulation of deubiquitination is closely related to the initiation and development of multiple cancers. Targeted regulation of deubiquitination has been recognized as an important strategy in tumor therapy. However, the mechanism by which drugs regulate deubiquitinase is not clear. Here, we identified ubiquitin-specific peptidase 48 (USP48), a member of the ubiquitin-specific protease family highly expressed in various tumors, as a specific substrate for the activated caspase-3. During drug induced apoptosis of AML cells, activated caspase-3 cleaves USP48 through recognizing the conservative motif DEQD located at 611-614 sites of human USP48. Subsequent analysis showed that the cleavage USP48 N-terminal fragment which contains catalytic active domain is easily degraded by ubiquitination. Meanwhile knockdown experiment showed that inhibiting the expression of USP48 could also promotes apoptosis and enhance the efficacy of chemotherapy drugs. Altogether, these results suggest that targeting USP48 may represent a novel therapeutic strategy in AML.

Keywords

Humans, Apoptosis, Leukemia, Myeloid, Acute, Caspase 3, Cell Line, Tumor, Ubiquitin-Specific Proteases, Antineoplastic Agents, Ubiquitination, AML, USP48, apoptosis, caspase 3, deubiquitination

DOI

10.1080/15384047.2025.2459426

PMID

39878157

PMCID

PMC11781246

PubMedCentral® Posted Date

1-29-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes