SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF
Abstract Background The gene encoding the E3 ubiquitin ligase substrate-binding adapter Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC); however, the molecular mechanisms underlying the contribution of SPOP mutations to tumorigenesis rem...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-12-01
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| Series: | Cell & Bioscience |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13578-022-00950-z |
| _version_ | 1797973495223681024 |
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| author | Kai Feng Qing Shi Dongyue Jiao Yingji Chen Wanqi Yang Ke Su Yalan Wang Yan Huang Pingzhao Zhang Yao Li Chenji Wang |
| author_facet | Kai Feng Qing Shi Dongyue Jiao Yingji Chen Wanqi Yang Ke Su Yalan Wang Yan Huang Pingzhao Zhang Yao Li Chenji Wang |
| author_sort | Kai Feng |
| collection | DOAJ |
| description | Abstract Background The gene encoding the E3 ubiquitin ligase substrate-binding adapter Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC); however, the molecular mechanisms underlying the contribution of SPOP mutations to tumorigenesis remain poorly understood. Methods BRAF harbors a potential SPOP-binding consensus motif (SBC) motif. Co-immunoprecipitation assays demonstrated that BRAF interacts with SPOP. A series of functional analyses in cell lines were performed to investigate the biological significance of MAPK/ERK activation caused by SPOP mutations. Results Cytoplasmic SPOP binds to and induces non-degradative ubiquitination of BRAF, thereby reducing the interaction between BRAF and other core components of the MAPK/ERK pathway. SPOP ablation increased MAPK/ERK activation. EC- or PCa-associated SPOP mutants showed a reduced capacity to bind and ubiquitinate BRAF. Moreover, cancer-associated BRAF mutations disrupted the BRAF-SPOP interaction and allowed BRAF to evade SPOP-mediated ubiquitination, thereby upregulating MAPK/ERK signaling and enhancing the neoplastic phenotypes of cancer cells. Conclusions Our findings provide new insights into the molecular link between SPOP mutation-driven tumorigenesis and aberrant BRAF-dependent activation of the MAPK/ERK pathway. |
| first_indexed | 2024-04-11T04:04:41Z |
| format | Article |
| id | doaj.art-f3cb1a688dc348af8c13bad65f6bb36a |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-04-11T04:04:41Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj.art-f3cb1a688dc348af8c13bad65f6bb36a2023-01-01T12:28:38ZengBMCCell & Bioscience2045-37012022-12-0112111510.1186/s13578-022-00950-zSPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAFKai Feng0Qing Shi1Dongyue Jiao2Yingji Chen3Wanqi Yang4Ke Su5Yalan Wang6Yan Huang7Pingzhao Zhang8Yao Li9Chenji Wang10Shanghai Stomatological Hospital & School of Stomatology, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan UniversityShanghai Stomatological Hospital & School of Stomatology, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan UniversityShanghai Stomatological Hospital & School of Stomatology, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan UniversityShanghai Stomatological Hospital & School of Stomatology, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan UniversityShanghai Stomatological Hospital & School of Stomatology, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan UniversityState Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan UniversityObstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan UniversityShanghai Stomatological Hospital & School of Stomatology, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan UniversityDepartment of Pathology, School of Basic Medical Sciences, Fudan University Shanghai Cancer Center, Fudan UniversityShanghai Stomatological Hospital & School of Stomatology, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan UniversityShanghai Stomatological Hospital & School of Stomatology, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan UniversityAbstract Background The gene encoding the E3 ubiquitin ligase substrate-binding adapter Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC); however, the molecular mechanisms underlying the contribution of SPOP mutations to tumorigenesis remain poorly understood. Methods BRAF harbors a potential SPOP-binding consensus motif (SBC) motif. Co-immunoprecipitation assays demonstrated that BRAF interacts with SPOP. A series of functional analyses in cell lines were performed to investigate the biological significance of MAPK/ERK activation caused by SPOP mutations. Results Cytoplasmic SPOP binds to and induces non-degradative ubiquitination of BRAF, thereby reducing the interaction between BRAF and other core components of the MAPK/ERK pathway. SPOP ablation increased MAPK/ERK activation. EC- or PCa-associated SPOP mutants showed a reduced capacity to bind and ubiquitinate BRAF. Moreover, cancer-associated BRAF mutations disrupted the BRAF-SPOP interaction and allowed BRAF to evade SPOP-mediated ubiquitination, thereby upregulating MAPK/ERK signaling and enhancing the neoplastic phenotypes of cancer cells. Conclusions Our findings provide new insights into the molecular link between SPOP mutation-driven tumorigenesis and aberrant BRAF-dependent activation of the MAPK/ERK pathway.https://doi.org/10.1186/s13578-022-00950-zSPOPBRAFMutationUbiquitinationMAPK/ERK |
| spellingShingle | Kai Feng Qing Shi Dongyue Jiao Yingji Chen Wanqi Yang Ke Su Yalan Wang Yan Huang Pingzhao Zhang Yao Li Chenji Wang SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF Cell & Bioscience SPOP BRAF Mutation Ubiquitination MAPK/ERK |
| title | SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF |
| title_full | SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF |
| title_fullStr | SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF |
| title_full_unstemmed | SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF |
| title_short | SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF |
| title_sort | spop inhibits braf dependent tumorigenesis through promoting non degradative ubiquitination of braf |
| topic | SPOP BRAF Mutation Ubiquitination MAPK/ERK |
| url | https://doi.org/10.1186/s13578-022-00950-z |
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