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

Abstract

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.

Citation

Luan, H., Mohapatra, B. C., Bielecki, T. A., Mushtaq, I., Mirza, S., Jennings, T. A., Clubb, R. J., An, W., Ahmed, D., El Ansari, R., Storck, M. D., Mishra, N. K., Guda, C., Sheinin, Y., Meza, J. L., Raja, S. M., Rakha, E., Band, V., & Band, H. (2018). Loss of the nuclear pool of ubiquitin ligase CHIP/STUB1 in breast cancer unleashes the MZF1-cathepsin pro-oncogenic program. Cancer Research, 78(10), 2524-2535. https://doi.org/10.1158/0008-5472.CAN-16-2140

• Journal Article Type: Article
• Acceptance Date: Feb 15, 2018
• Online Publication Date: Mar 6, 2018
• Publication Date: May 15, 2018
• Deposit Date: Feb 27, 2018
• Publicly Available Date: Mar 7, 2019
• Journal: Cancer Research
• Print ISSN: 0008-5472
• Electronic ISSN: 1538-7445
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 78
• Issue: 10
• Pages: 2524-2535
• DOI: https://doi.org/10.1158/0008-5472.CAN-16-2140
• Keywords: CHIP/STUB1, ubiquitin ligase, breast cancer, ErbB2, matrix degradation
• Public URL: https://nottingham-repository.worktribe.com/output/918812
• Publisher URL: http://cancerres.aacrjournals.org/content/78/10/2524
• Contract Date: Feb 27, 2018