Biochimica et biophysica acta. Molecular basis of disease · 2025
Ubiquitin-specific peptidase 40 promotes cellular proliferation and inhibits apoptosis through deubiquitination-mediated stabilization of c-MYC in acute myeloid leukemia.
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Fu Wen, Wu Qiaoliang, Yao Yanru, Sun Yingsen, Wang Huafang, Jie Jing, Zheng Xiaoyan, Wang Lina, Hu Xiaoge, Tong Xiangmin, Xu Qiuran
Аннотация
BACKGROUND: Ubiquitin-specific peptidase 40(USP40), a member of the deubiquitinase family, regulates numerous cellular processes. Recent studies have increasingly highlighted the involvement of USP40 in cancer development. However, the precise mechanism through which USP40 influences acute myeloid leukemia (AML) progression remains poorly understood.
METHODS: The expression levels of USP40 in AML tissues and cell lines were examined using Gene Expression Profiling Interactive Analysis, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and western blotting (WB). The Kaplan-Meier plotter was used to evaluate the association between USP40 expression and prognosis in patients with AML. Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine incorporation, apoptosis assays, and subcutaneous tumor models in nude mice were applied to determine the effects of USP40 expression on AML cell proliferation and apoptosis in vitro and in vivo. WB, RT-qPCR, immunofluorescence assay, co-immunoprecipitation assay, and cycloheximide chase assay were conducted to explore the relationship between USP40 and c-MYC. Rescue experiments were further performed to assess the functional contribution of USP40-c-MYC axis to AML progression.
RESULTS: USP40 was overexpressed in AML tissues and cell lines compared to normal controls and correlated with poor prognosis. USP40 accelerated AML progression by promoting proliferation and inhibiting apoptosis. Mechanistically, USP40 deubiquitinated c-MYC by selectively removing K48-linked polyubiquitin chains, thereby preventing its degradation via the ubiquitin-proteasome pathway.
CONCLUSION: USP40 accelerated AML progression by deubiquitinating c-MYC, highlighting the USP40-c-MYC axis as a potential therapeutic target for AML treatment.
METHODS: The expression levels of USP40 in AML tissues and cell lines were examined using Gene Expression Profiling Interactive Analysis, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and western blotting (WB). The Kaplan-Meier plotter was used to evaluate the association between USP40 expression and prognosis in patients with AML. Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine incorporation, apoptosis assays, and subcutaneous tumor models in nude mice were applied to determine the effects of USP40 expression on AML cell proliferation and apoptosis in vitro and in vivo. WB, RT-qPCR, immunofluorescence assay, co-immunoprecipitation assay, and cycloheximide chase assay were conducted to explore the relationship between USP40 and c-MYC. Rescue experiments were further performed to assess the functional contribution of USP40-c-MYC axis to AML progression.
RESULTS: USP40 was overexpressed in AML tissues and cell lines compared to normal controls and correlated with poor prognosis. USP40 accelerated AML progression by promoting proliferation and inhibiting apoptosis. Mechanistically, USP40 deubiquitinated c-MYC by selectively removing K48-linked polyubiquitin chains, thereby preventing its degradation via the ubiquitin-proteasome pathway.
CONCLUSION: USP40 accelerated AML progression by deubiquitinating c-MYC, highlighting the USP40-c-MYC axis as a potential therapeutic target for AML treatment.