The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein
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 s...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2019-08-01
|
| Series: | Cancer Cell International |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12935-019-0936-5 |
| _version_ | 1818304911410987008 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Lanqin Wu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T06:18:13Z |
| format | Article |
| id | doaj.art-6eec4a7e3a2541e58db7b0c14e20f195 |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-12-13T06:18:13Z |
| publishDate | 2019-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-6eec4a7e3a2541e58db7b0c14e20f1952022-12-21T23:56:55ZengBMCCancer Cell International1475-28672019-08-0119111110.1186/s12935-019-0936-5The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 proteinLanqin Wu0Yingying Lin1Jinan Feng2Yuanlin Qi3Xinrui Wang4Qiaofa Lin5Wanyan Shi6Enrun Zheng7Wei Wang8Zhenzhu Hou9Hanbin Lin10Cheng Yu11Yan He12Yan Xu13Hong Yang14Ling Lin15Lisheng Li16The School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityState Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to School of Medicine, Shanghai Jiao Tong UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityAbstract 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.http://link.springer.com/article/10.1186/s12935-019-0936-5Deubiquitinating enzymeOTUD1MCL1BH3-mimetic inhibitor |
| spellingShingle | 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 The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein Cancer Cell International Deubiquitinating enzyme OTUD1 MCL1 BH3-mimetic inhibitor |
| title | The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein |
| title_full | The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein |
| title_fullStr | The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein |
| title_full_unstemmed | The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein |
| title_short | The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein |
| title_sort | deubiquitinating enzyme otud1 antagonizes bh3 mimetic inhibitor induced cell death through regulating the stability of the mcl1 protein |
| topic | Deubiquitinating enzyme OTUD1 MCL1 BH3-mimetic inhibitor |
| url | http://link.springer.com/article/10.1186/s12935-019-0936-5 |
| work_keys_str_mv | AT lanqinwu thedeubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT yingyinglin thedeubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT jinanfeng thedeubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT yuanlinqi thedeubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT xinruiwang thedeubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT qiaofalin thedeubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT wanyanshi thedeubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT enrunzheng thedeubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT weiwang thedeubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT zhenzhuhou thedeubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT hanbinlin thedeubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT chengyu thedeubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT yanhe thedeubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT yanxu thedeubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT hongyang thedeubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT linglin thedeubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT lishengli thedeubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT lanqinwu deubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT yingyinglin deubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT jinanfeng deubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT yuanlinqi deubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT xinruiwang deubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT qiaofalin deubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT wanyanshi deubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT enrunzheng deubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT weiwang deubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT zhenzhuhou deubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT hanbinlin deubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT chengyu deubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT yanhe deubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT yanxu deubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT hongyang deubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT linglin deubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein AT lishengli deubiquitinatingenzymeotud1antagonizesbh3mimeticinhibitorinducedcelldeaththroughregulatingthestabilityofthemcl1protein |