Loss of the nuclear pool of ubiquitin ligase CHIP/STUB1 in breast cancer unleashes the MZF1-cathepsin pro-oncogenic program
CHIP/STUB1 ubiquitin ligase is a negative co-chaperone for HSP90/HSC70, and its expression is reduced or lost in several cancers, including breast cancer. Using an extensive and well-annotated breast cancer tissue collection, we identified the loss of nuclear but not cytoplasmic CHIP to predict more...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Association for Cancer Research
2018
|
| Subjects: | |
| Online Access: | https://eprints.nottingham.ac.uk/50047/ |
| _version_ | 1848798138830159872 |
|---|---|
| author | Luan, Haitao Mohapatra, Bhopal C. Bielecki, Timothy A. Mushtaq, Insha Mirza, Sameer Jennings, Tameka A. Clubb, Robert J. An, Wei Ahmed, Dena El Ansari, Rokaya Storck, Matthew D. Mishra, Nitish K. Guda, Chittibabu Sheinin, Yuri Meza, Jane L. Raja, Srikumar M. Rakha, Emad Band, Vimla Band, Hamid |
| author_facet | Luan, Haitao Mohapatra, Bhopal C. Bielecki, Timothy A. Mushtaq, Insha Mirza, Sameer Jennings, Tameka A. Clubb, Robert J. An, Wei Ahmed, Dena El Ansari, Rokaya Storck, Matthew D. Mishra, Nitish K. Guda, Chittibabu Sheinin, Yuri Meza, Jane L. Raja, Srikumar M. Rakha, Emad Band, Vimla Band, Hamid |
| author_sort | Luan, Haitao |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | CHIP/STUB1 ubiquitin ligase is a negative co-chaperone for HSP90/HSC70, and its expression is reduced or lost in several cancers, including breast cancer. Using an extensive and well-annotated breast cancer tissue collection, we identified the loss of nuclear but not cytoplasmic CHIP to predict more aggressive tumorigenesis and shorter patient survival, with loss of CHIP in two-thirds of ErbB2+ and triple-negative breast cancers and in one-third of ER+ breast cancers. Reduced CHIP expression was seen in breast cancer patient-derived xenograft tumors and in ErbB2+ and triple-negative breast cancer cell lines. Ectopic CHIP expression in ErbB2+ lines suppressed in vitro oncogenic traits and in vivo xenograft tumor growth. An unbiased screen for CHIP-regulated nuclear transcription factors identified many candidates whose DNA-binding activity was up-or down-regulated by CHIP. We characterized Myeloid Zinc Finger 1 (MZF1) as a CHIP target given its recently identified role as a positive regulator of cathepsin B/L (CTSB/L)-mediated tumor cell invasion downstream of ErbB2. We show that CHIP negatively regulates CTSB/L expression in ErbB2+ and other breast cancer cell lines. CTSB inhibition abrogates invasion and matrix degradation in vitro and halts ErbB2+ breast cancer cell line xenograft growth. We conclude that loss of CHIP remodels the cellular transcriptome to unleash critical pro-oncogenic pathways, such as the matrix-degrading enzymes of the cathepsin family, whose components can provide new therapeutic opportunities in breast and other cancers with loss of CHIP expression. |
| first_indexed | 2025-11-14T20:15:01Z |
| format | Article |
| id | nottingham-50047 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T20:15:01Z |
| publishDate | 2018 |
| publisher | American Association for Cancer Research |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-500472019-03-06T04:30:16Z https://eprints.nottingham.ac.uk/50047/ Loss of the nuclear pool of ubiquitin ligase CHIP/STUB1 in breast cancer unleashes the MZF1-cathepsin pro-oncogenic program Luan, Haitao Mohapatra, Bhopal C. Bielecki, Timothy A. Mushtaq, Insha Mirza, Sameer Jennings, Tameka A. Clubb, Robert J. An, Wei Ahmed, Dena El Ansari, Rokaya Storck, Matthew D. Mishra, Nitish K. Guda, Chittibabu Sheinin, Yuri Meza, Jane L. Raja, Srikumar M. Rakha, Emad Band, Vimla Band, Hamid CHIP/STUB1 ubiquitin ligase is a negative co-chaperone for HSP90/HSC70, and its expression is reduced or lost in several cancers, including breast cancer. Using an extensive and well-annotated breast cancer tissue collection, we identified the loss of nuclear but not cytoplasmic CHIP to predict more aggressive tumorigenesis and shorter patient survival, with loss of CHIP in two-thirds of ErbB2+ and triple-negative breast cancers and in one-third of ER+ breast cancers. Reduced CHIP expression was seen in breast cancer patient-derived xenograft tumors and in ErbB2+ and triple-negative breast cancer cell lines. Ectopic CHIP expression in ErbB2+ lines suppressed in vitro oncogenic traits and in vivo xenograft tumor growth. An unbiased screen for CHIP-regulated nuclear transcription factors identified many candidates whose DNA-binding activity was up-or down-regulated by CHIP. We characterized Myeloid Zinc Finger 1 (MZF1) as a CHIP target given its recently identified role as a positive regulator of cathepsin B/L (CTSB/L)-mediated tumor cell invasion downstream of ErbB2. We show that CHIP negatively regulates CTSB/L expression in ErbB2+ and other breast cancer cell lines. CTSB inhibition abrogates invasion and matrix degradation in vitro and halts ErbB2+ breast cancer cell line xenograft growth. We conclude that loss of CHIP remodels the cellular transcriptome to unleash critical pro-oncogenic pathways, such as the matrix-degrading enzymes of the cathepsin family, whose components can provide new therapeutic opportunities in breast and other cancers with loss of CHIP expression. American Association for Cancer Research 2018-03-06 Article PeerReviewed application/pdf en https://eprints.nottingham.ac.uk/50047/1/Luan%20et%20al%20CHIP-MZF1-CTSB-L%20Cancer%20Research%20Revision%20final%202%2026%2018.pdf Luan, Haitao, Mohapatra, Bhopal C., Bielecki, Timothy A., Mushtaq, Insha, Mirza, Sameer, Jennings, Tameka A., Clubb, Robert J., An, Wei, Ahmed, Dena, El Ansari, Rokaya, Storck, Matthew D., Mishra, Nitish K., Guda, Chittibabu, Sheinin, Yuri, Meza, Jane L., Raja, Srikumar M., Rakha, Emad, Band, Vimla and Band, Hamid (2018) Loss of the nuclear pool of ubiquitin ligase CHIP/STUB1 in breast cancer unleashes the MZF1-cathepsin pro-oncogenic program. Cancer Research . ISSN 1538-7445 CHIP/STUB1 ubiquitin ligase breast cancer ErbB2 matrix degradation http://cancerres.aacrjournals.org/content/early/2018/03/06/0008-5472.CAN-16-2140 doi:10.1158/0008-5472.CAN-16-2140 doi:10.1158/0008-5472.CAN-16-2140 |
| spellingShingle | CHIP/STUB1 ubiquitin ligase breast cancer ErbB2 matrix degradation Luan, Haitao Mohapatra, Bhopal C. Bielecki, Timothy A. Mushtaq, Insha Mirza, Sameer Jennings, Tameka A. Clubb, Robert J. An, Wei Ahmed, Dena El Ansari, Rokaya Storck, Matthew D. Mishra, Nitish K. Guda, Chittibabu Sheinin, Yuri Meza, Jane L. Raja, Srikumar M. Rakha, Emad Band, Vimla Band, Hamid Loss of the nuclear pool of ubiquitin ligase CHIP/STUB1 in breast cancer unleashes the MZF1-cathepsin pro-oncogenic program |
| title | Loss of the nuclear pool of ubiquitin ligase CHIP/STUB1 in breast cancer unleashes the MZF1-cathepsin pro-oncogenic program |
| title_full | Loss of the nuclear pool of ubiquitin ligase CHIP/STUB1 in breast cancer unleashes the MZF1-cathepsin pro-oncogenic program |
| title_fullStr | Loss of the nuclear pool of ubiquitin ligase CHIP/STUB1 in breast cancer unleashes the MZF1-cathepsin pro-oncogenic program |
| title_full_unstemmed | Loss of the nuclear pool of ubiquitin ligase CHIP/STUB1 in breast cancer unleashes the MZF1-cathepsin pro-oncogenic program |
| title_short | Loss of the nuclear pool of ubiquitin ligase CHIP/STUB1 in breast cancer unleashes the MZF1-cathepsin pro-oncogenic program |
| title_sort | loss of the nuclear pool of ubiquitin ligase chip/stub1 in breast cancer unleashes the mzf1-cathepsin pro-oncogenic program |
| topic | CHIP/STUB1 ubiquitin ligase breast cancer ErbB2 matrix degradation |
| url | https://eprints.nottingham.ac.uk/50047/ https://eprints.nottingham.ac.uk/50047/ https://eprints.nottingham.ac.uk/50047/ |