The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein
| Autor: | Xinrui Wang, Cheng Yu, Zhenzhu Hou, Hong Yang, Lisheng Li, Yan Xu, Enrun Zheng, Yan He, Qiaofa Lin, Yingying Lin, Yuanlin Qi, Wanyan Shi, Lanqin Wu, Hanbin Lin, Ling Lin, Wei Wang, Jinan Feng |
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| Rok vydání: | 2019 |
| Předmět: |
Cancer Research
Programmed cell death Immunoprecipitation BH3-mimetic inhibitor Cell lcsh:RC254-282 Deubiquitinating enzyme 03 medical and health sciences 0302 clinical medicine Ubiquitin Genetics medicine MCL1 Viability assay lcsh:QH573-671 biology lcsh:Cytology Chemistry Cancer lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease Cell biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis biology.protein OTUD1 Primary Research |
| Zdroj: | Cancer Cell International, Vol 19, Iss 1, Pp 1-11 (2019) Cancer Cell International |
| ISSN: | 1475-2867 |
| Popis: | Background Myeloid cell leukaemia 1 (MCL1) is a pro-survival Bcl-2 family protein that plays important roles in cell survival, proliferation, differentiation and tumourigenesis. MCL1 is a fast-turnover protein that is degraded via an ubiquitination/proteasome-dependent mechanism. Although several E3 ligases have been discovered to promote the ubiquitination of MCL1, the deubiquitinating enzyme (DUB) that regulates its stability requires further investigation. Methods The immunoprecipitation was used to determine the interaction between OTUD1 and MCL1. The ubiquitination assays was performed to determine the regulation of MCL1 by OTUD1. The cell viability was used to determine the regulation of BH3-mimetic inhibitor induced cell death by OTUD1. The survival analysis was used to determine the relationship between OTUD1 expression levels and the survival rate of cancer patients. Results By screening a DUB expression library, we determined that the deubiquitinating enzyme OTUD1 regulates MCL1 protein stability in an enzymatic-activity dependent manner. OTUD1 interacts with MCL1 and promotes its deubiquitination. Knockdown of OTUD1 increases the sensitivity of tumour cells to the BH3-mimetic inhibitor ABT-263, while overexpression of OTUD1 increases tumour cell tolerance of ABT-263. Furthermore, bioinformatics analysis data reveal that OTUD1 is a negative prognostic factor for liver cancer, ovarian cancer and specific subtypes of breast and cervical cancer. Conclusions The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein. Thus, OTUD1 could be considered as a therapeutic target for curing these cancers. |
| Databáze: | OpenAIRE |
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