CHIP/STUB1 Ubiquitin Ligase Functions as a Negative Regulator of ErbB2 by Promoting Its Early Post-Biosynthesis Degradation
Overexpression of the epidermal growth factor receptor (EGFR) family member ErbB2 (HER2) drives oncogenesis in up to 25% of invasive breast cancers. ErbB2 expression at the cell surface is required for oncogenesis but mechanisms that ensure the optimal cell surface display of overexpressed ErbB2 fol...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/16/3936 |
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| author | Haitao Luan Tameka A. Bailey Robert J. Clubb Bhopal C. Mohapatra Aaqib M. Bhat Sukanya Chakraborty Namista Islam Insha Mushtaq Matthew D. Storck Srikumar M. Raja Vimla Band Hamid Band |
| author_facet | Haitao Luan Tameka A. Bailey Robert J. Clubb Bhopal C. Mohapatra Aaqib M. Bhat Sukanya Chakraborty Namista Islam Insha Mushtaq Matthew D. Storck Srikumar M. Raja Vimla Band Hamid Band |
| author_sort | Haitao Luan |
| collection | DOAJ |
| description | Overexpression of the epidermal growth factor receptor (EGFR) family member ErbB2 (HER2) drives oncogenesis in up to 25% of invasive breast cancers. ErbB2 expression at the cell surface is required for oncogenesis but mechanisms that ensure the optimal cell surface display of overexpressed ErbB2 following its biosynthesis in the endoplasmic reticulum are poorly understood. ErbB2 is dependent on continuous association with HSP90 molecular chaperone for its stability and function as an oncogenic driver. Here, we use knockdown and overexpression studies to show that the HSP90/HSC70-interacting negative co-chaperone CHIP (C-terminus of HSC70-Interacting protein)/STUB1 (STIP1-homologous U-Box containing protein 1) targets the newly synthesized, HSP90/HSC70-associated, ErbB2 for ubiquitin/proteasome-dependent degradation in the endoplasmic reticulum and Golgi, thus identifying a novel mechanism that negatively regulates cell surface ErbB2 levels in breast cancer cells, consistent with frequent loss of CHIP expression previously reported in ErbB2-overexpressing breast cancers. ErbB2-overexpressing breast cancer cells with low CHIP expression exhibited higher endoplasmic reticulum stress inducibility. Accordingly, the endoplasmic reticulum stress-inducing anticancer drug Bortezomib combined with ErbB2-targeted humanized antibody Trastuzumab showed synergistic inhibition of ErbB2-overexpressing breast cancer cell proliferation. Our findings reveal new insights into mechanisms that control the surface expression of overexpressed ErbB2 and suggest that reduced CHIP expression may specify ErbB2-overexpressing breast cancers suitable for combined treatment with Trastuzumab and ER stress inducing agents. |
| first_indexed | 2024-03-10T08:57:52Z |
| format | Article |
| id | doaj.art-c0f18ebf17a04c0aa1b85f09bcc9bdc7 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T08:57:52Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-c0f18ebf17a04c0aa1b85f09bcc9bdc72023-11-22T07:01:23ZengMDPI AGCancers2072-66942021-08-011316393610.3390/cancers13163936CHIP/STUB1 Ubiquitin Ligase Functions as a Negative Regulator of ErbB2 by Promoting Its Early Post-Biosynthesis DegradationHaitao Luan0Tameka A. Bailey1Robert J. Clubb2Bhopal C. Mohapatra3Aaqib M. Bhat4Sukanya Chakraborty5Namista Islam6Insha Mushtaq7Matthew D. Storck8Srikumar M. Raja9Vimla Band10Hamid Band11Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USAEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USAEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USAEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USADepartments of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USADepartments of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USADepartments of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USADepartments of Pathology & Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USAEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USAEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USADepartments of Genetics, Cell Biology & Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USAEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USAOverexpression of the epidermal growth factor receptor (EGFR) family member ErbB2 (HER2) drives oncogenesis in up to 25% of invasive breast cancers. ErbB2 expression at the cell surface is required for oncogenesis but mechanisms that ensure the optimal cell surface display of overexpressed ErbB2 following its biosynthesis in the endoplasmic reticulum are poorly understood. ErbB2 is dependent on continuous association with HSP90 molecular chaperone for its stability and function as an oncogenic driver. Here, we use knockdown and overexpression studies to show that the HSP90/HSC70-interacting negative co-chaperone CHIP (C-terminus of HSC70-Interacting protein)/STUB1 (STIP1-homologous U-Box containing protein 1) targets the newly synthesized, HSP90/HSC70-associated, ErbB2 for ubiquitin/proteasome-dependent degradation in the endoplasmic reticulum and Golgi, thus identifying a novel mechanism that negatively regulates cell surface ErbB2 levels in breast cancer cells, consistent with frequent loss of CHIP expression previously reported in ErbB2-overexpressing breast cancers. ErbB2-overexpressing breast cancer cells with low CHIP expression exhibited higher endoplasmic reticulum stress inducibility. Accordingly, the endoplasmic reticulum stress-inducing anticancer drug Bortezomib combined with ErbB2-targeted humanized antibody Trastuzumab showed synergistic inhibition of ErbB2-overexpressing breast cancer cell proliferation. Our findings reveal new insights into mechanisms that control the surface expression of overexpressed ErbB2 and suggest that reduced CHIP expression may specify ErbB2-overexpressing breast cancers suitable for combined treatment with Trastuzumab and ER stress inducing agents.https://www.mdpi.com/2072-6694/13/16/3936CHIP/STUB1ubiquitinubiquitin ligaseE3breast cancerErbB2 |
| spellingShingle | Haitao Luan Tameka A. Bailey Robert J. Clubb Bhopal C. Mohapatra Aaqib M. Bhat Sukanya Chakraborty Namista Islam Insha Mushtaq Matthew D. Storck Srikumar M. Raja Vimla Band Hamid Band CHIP/STUB1 Ubiquitin Ligase Functions as a Negative Regulator of ErbB2 by Promoting Its Early Post-Biosynthesis Degradation Cancers CHIP/STUB1 ubiquitin ubiquitin ligase E3 breast cancer ErbB2 |
| title | CHIP/STUB1 Ubiquitin Ligase Functions as a Negative Regulator of ErbB2 by Promoting Its Early Post-Biosynthesis Degradation |
| title_full | CHIP/STUB1 Ubiquitin Ligase Functions as a Negative Regulator of ErbB2 by Promoting Its Early Post-Biosynthesis Degradation |
| title_fullStr | CHIP/STUB1 Ubiquitin Ligase Functions as a Negative Regulator of ErbB2 by Promoting Its Early Post-Biosynthesis Degradation |
| title_full_unstemmed | CHIP/STUB1 Ubiquitin Ligase Functions as a Negative Regulator of ErbB2 by Promoting Its Early Post-Biosynthesis Degradation |
| title_short | CHIP/STUB1 Ubiquitin Ligase Functions as a Negative Regulator of ErbB2 by Promoting Its Early Post-Biosynthesis Degradation |
| title_sort | chip stub1 ubiquitin ligase functions as a negative regulator of erbb2 by promoting its early post biosynthesis degradation |
| topic | CHIP/STUB1 ubiquitin ubiquitin ligase E3 breast cancer ErbB2 |
| url | https://www.mdpi.com/2072-6694/13/16/3936 |
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