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Updated: May 7, 2026
Method for Measuring the Activity of Deubiquitinating Enzymes in Cell Lines and Tissue Samples
Published on: May 10, 2015
DUB3 is a MAGEA3 deubiquitinase and a potential therapeutic target in hepatocellular carcinoma
Yuanhong Chen1, Feng Gao1, Yan He1
1National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430074, China.
Abstract:
Although melanoma-associated antigen A3 and A6 (MAGEA3/6)-specific tumor vaccines have shown antitumor effects in melanoma and non-small cell lung cancer (NSCLC), many cancers do not respond because MAGEA3 can promote cancer without triggering an immune response. Here, we identified DUB3 as the MAGEA3 deubiquitinase. DUB3 interacts with, deubiquitinates and stabilizes MAGEA3. Depletion of DUB3 in hepatocellular carcinoma (HCC) cells results in MAGEA3 degradation and P53-dependent growth inhibition. Moreover, DUB3 knockout attenuates HCC tumorigenesis in vivo, which can be rescued by restoration of MAGEA3. Intriguingly, pharmacological inhibition of DUB3 by palbociclib promotes degradation of MAGEA3 and inhibits tumor growth in preclinical models implanted with parental HCC cells but not with DUB3 knockout HCC cells. In patients with HCC, DUB3 is highly expressed, and its levels positively correlate with MAGEA3 levels. Taken together, DUB3 is a MAGEA3 deubiquitinase, and abrogating DUB3 enzymatic activity by palbociclib is a promising therapeutic strategy for HCC.
Insights
DUB3 stabilizes MAGEA3, promoting hepatocellular carcinoma (HCC) growth. Inhibiting DUB3 with palbociclib degrades MAGEA3, offering a promising therapeutic strategy for HCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Melanoma-associated antigen A3 (MAGEA3) promotes cancer without immune response, limiting vaccine efficacy.
- MAGEA3 stabilization is crucial for its oncogenic function in various cancers.
Purpose of the Study:
- To identify the deubiquitinase responsible for MAGEA3 stabilization.
- To investigate the therapeutic potential of targeting this deubiquitinase in hepatocellular carcinoma (HCC).
Main Methods:
- Identified DUB3 as the MAGEA3 deubiquitinase through interaction and deubiquitination assays.
- Utilized DUB3 depletion and knockout models in HCC cells and in vivo.
- Administered palbociclib, a pharmacological inhibitor of DUB3, in preclinical HCC models.
Main Results:
- DUB3 directly interacts with, deubiquitinates, and stabilizes MAGEA3.
- DUB3 depletion in HCC cells leads to MAGEA3 degradation and P53-dependent growth inhibition.
- DUB3 knockout attenuates HCC tumorigenesis, which is rescued by MAGEA3 restoration.
- Palbociclib treatment inhibits tumor growth in MAGEA3-expressing HCC models by promoting MAGEA3 degradation.
- High DUB3 expression in HCC patients correlates positively with MAGEA3 levels.
Conclusions:
- DUB3 functions as a MAGEA3 deubiquitinase, stabilizing MAGEA3 and promoting HCC.
- Pharmacological inhibition of DUB3's enzymatic activity by palbociclib is a potential therapeutic strategy for HCC.
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