Hypoxia-induced circWSB1 promotes breast cancer progression through destabilizing p53 by interacting with USP10
Abstract Background Hypoxia has long been considered as a hallmark of solid tumors and is closely associated with tumor progression. Circular RNAs (circRNAs) have been identified as a critical modulator in various cancers. However, the connections between hypoxia and circRNAs are largely unknown. Me...
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| Format: | Article |
| Language: | English |
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BMC
2022-03-01
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| Series: | Molecular Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12943-022-01567-z |
| _version_ | 1819025204476641280 |
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| author | Rui Yang Hang Chen Lei Xing Bin Wang Mengting Hu Xiaoqiang Ou Hong Chen Yumei Deng Dawei Liu Rong Jiang Junxia Chen |
| author_facet | Rui Yang Hang Chen Lei Xing Bin Wang Mengting Hu Xiaoqiang Ou Hong Chen Yumei Deng Dawei Liu Rong Jiang Junxia Chen |
| author_sort | Rui Yang |
| collection | DOAJ |
| description | Abstract Background Hypoxia has long been considered as a hallmark of solid tumors and is closely associated with tumor progression. Circular RNAs (circRNAs) have been identified as a critical modulator in various cancers. However, the connections between hypoxia and circRNAs are largely unknown. Methods Here, we investigated the expression profile of circRNAs in breast cancer (BC) MCF-7 cells under hypoxia and normoxia using microarray. We identified a novel hypoxia-responsive circRNA named circWSB1, whose expression pattern, potential diagnostic value and prognostic significance were assessed by qRT-PCR and in situ hybridization. Loss- and gain-of-function investigations in vivo and in vitro were performed to determine the biological functions of circWSB1. Mechanistically, chromatin immunoprecipitation and dual luciferase reporter assays were carried out to analyze the biogenesis of circWSB1. Furthermore, biotin-labeled RNA pull-down, mass spectrometry, RNA immunoprecipitation, fluorescent in situ hybridization, RNA electrophoretic mobility shift, deletion-mapping, co-immunoprecipitation assays and rescue experiments were applied to investigate the interaction between circWSB1 and Ubiquitin-specific peptidase 10 (USP10) as well as the relationship between USP10 and p53. Results We found that the expression of circWSB1 was significantly upregulated in BC tissues and correlated with poor clinical outcomes, which might serve as an independent prognostic factor for BC patients. Ectopic expression of circWSB1 promoted the proliferation of BC cell in vitro and in vivo. Mechanistically, circWSB1 was transcriptionally upregulated by HIF1α in response to hypoxia and could competitively bind to deubiquitinase USP10 to prevent the access of p53 to USP10 in BC cells, leading to degradation of p53 and tumor progression of BC. Conclusions Taken together, our findings disclose a novel mechanism that hypoxia-inducible circWSB1 could interact with USP10 to attenuate USP10 mediated p53 stabilization and promote the progression of BC, providing an alternative prognostic biomarker and therapeutic target for BC. |
| first_indexed | 2024-12-21T05:06:58Z |
| format | Article |
| id | doaj.art-f8fce120c08b440bb9c326cdbf60dbe7 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-21T05:06:58Z |
| publishDate | 2022-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-f8fce120c08b440bb9c326cdbf60dbe72022-12-21T19:15:08ZengBMCMolecular Cancer1476-45982022-03-0121112010.1186/s12943-022-01567-zHypoxia-induced circWSB1 promotes breast cancer progression through destabilizing p53 by interacting with USP10Rui Yang0Hang Chen1Lei Xing2Bin Wang3Mengting Hu4Xiaoqiang Ou5Hong Chen6Yumei Deng7Dawei Liu8Rong Jiang9Junxia Chen10Department of Cell Biology and Genetics, Chongqing Medical UniversityDepartment of Cell Biology and Genetics, Chongqing Medical UniversityDepartment of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Cell Biology and Genetics, Chongqing Medical UniversityDepartment of Cell Biology and Genetics, Chongqing Medical UniversityDepartment of Cell Biology and Genetics, Chongqing Medical UniversityDepartment of Cell Biology and Genetics, Chongqing Medical UniversityDepartment of Cell Biology and Genetics, Chongqing Medical UniversityDepartment of Anesthesiology, Yongchuan Hospital of Chongqing Medical UniversityLaboratory of Stem Cells and Tissue Engineering, Chongqing Medical UniversityDepartment of Cell Biology and Genetics, Chongqing Medical UniversityAbstract Background Hypoxia has long been considered as a hallmark of solid tumors and is closely associated with tumor progression. Circular RNAs (circRNAs) have been identified as a critical modulator in various cancers. However, the connections between hypoxia and circRNAs are largely unknown. Methods Here, we investigated the expression profile of circRNAs in breast cancer (BC) MCF-7 cells under hypoxia and normoxia using microarray. We identified a novel hypoxia-responsive circRNA named circWSB1, whose expression pattern, potential diagnostic value and prognostic significance were assessed by qRT-PCR and in situ hybridization. Loss- and gain-of-function investigations in vivo and in vitro were performed to determine the biological functions of circWSB1. Mechanistically, chromatin immunoprecipitation and dual luciferase reporter assays were carried out to analyze the biogenesis of circWSB1. Furthermore, biotin-labeled RNA pull-down, mass spectrometry, RNA immunoprecipitation, fluorescent in situ hybridization, RNA electrophoretic mobility shift, deletion-mapping, co-immunoprecipitation assays and rescue experiments were applied to investigate the interaction between circWSB1 and Ubiquitin-specific peptidase 10 (USP10) as well as the relationship between USP10 and p53. Results We found that the expression of circWSB1 was significantly upregulated in BC tissues and correlated with poor clinical outcomes, which might serve as an independent prognostic factor for BC patients. Ectopic expression of circWSB1 promoted the proliferation of BC cell in vitro and in vivo. Mechanistically, circWSB1 was transcriptionally upregulated by HIF1α in response to hypoxia and could competitively bind to deubiquitinase USP10 to prevent the access of p53 to USP10 in BC cells, leading to degradation of p53 and tumor progression of BC. Conclusions Taken together, our findings disclose a novel mechanism that hypoxia-inducible circWSB1 could interact with USP10 to attenuate USP10 mediated p53 stabilization and promote the progression of BC, providing an alternative prognostic biomarker and therapeutic target for BC.https://doi.org/10.1186/s12943-022-01567-zHypoxiacircWSB1Breast cancerp53USP10 |
| spellingShingle | Rui Yang Hang Chen Lei Xing Bin Wang Mengting Hu Xiaoqiang Ou Hong Chen Yumei Deng Dawei Liu Rong Jiang Junxia Chen Hypoxia-induced circWSB1 promotes breast cancer progression through destabilizing p53 by interacting with USP10 Molecular Cancer Hypoxia circWSB1 Breast cancer p53 USP10 |
| title | Hypoxia-induced circWSB1 promotes breast cancer progression through destabilizing p53 by interacting with USP10 |
| title_full | Hypoxia-induced circWSB1 promotes breast cancer progression through destabilizing p53 by interacting with USP10 |
| title_fullStr | Hypoxia-induced circWSB1 promotes breast cancer progression through destabilizing p53 by interacting with USP10 |
| title_full_unstemmed | Hypoxia-induced circWSB1 promotes breast cancer progression through destabilizing p53 by interacting with USP10 |
| title_short | Hypoxia-induced circWSB1 promotes breast cancer progression through destabilizing p53 by interacting with USP10 |
| title_sort | hypoxia induced circwsb1 promotes breast cancer progression through destabilizing p53 by interacting with usp10 |
| topic | Hypoxia circWSB1 Breast cancer p53 USP10 |
| url | https://doi.org/10.1186/s12943-022-01567-z |
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