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01.12.2019 | Primary research | Ausgabe 1/2019 Open Access

Cancer Cell International 1/2019

The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein

Zeitschrift:
Cancer Cell International > Ausgabe 1/2019
Autoren:
Lanqin Wu, Yingying Lin, Jinan Feng, Yuanlin Qi, Xinrui Wang, Qiaofa Lin, Wanyan Shi, Enrun Zheng, Wei Wang, Zhenzhu Hou, Hanbin Lin, Cheng Yu, Yan He, Yan Xu, Hong Yang, Ling Lin, Lisheng Li
Wichtige Hinweise
Lanqin Wu, Yingying Lin, Jinan Feng and Yuanlin Qi are co-first authors

Supplementary information

Supplementary information accompanies this paper at https://​doi.​org/​10.​1186/​s12935-019-0936-5.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Abstract

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.
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