Loss of the nuclear pool of Ubiquitin ligase CHIP/STUB1 in breast cancer unleashes the MZF1-cathepsin pro-oncogenic program

Haitao Luan, Bhopal Mohapatra, Timothy A. Bielecki, Insha Mushtaq, Sameer Mirza, Tameka A. Jennings, Robert J. Clubb, Wei An, Dena Ahmed, Rokaya El-Ansari, Matthew D. Storck, Nitish K. Mishra, Chittibabu Guda, Yuri M. Sheinin, Jane L Meza, Srikumar Raja, Emad A. Rakha, Vimla Band, Hamid Band

Research output: Contribution to journalArticle

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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 ErbB2þ and triple-negative breast cancers (TNBC) and in one third of ERþ breast cancers. Reduced CHIP expression was seen in breast cancer patient-derived xenograft tumors and in ErbB2þ and TNBC cell lines. Ectopic CHIP expression in ErbB2þ 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 downregulated 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 ErbB2þ and other breast cancer cell lines. CTSB inhibition abrogates invasion and matrix degradation in vitro and halts ErbB2þ 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. Significance: These findings reveal a novel targetable pathway of breast oncogenesis unleashed by the loss of tumor suppressor ubiquitin ligase CHIP/STUB1.

Original languageEnglish (US)
Pages (from-to)2524-2535
Number of pages12
JournalCancer Research
Volume78
Issue number10
DOIs
StatePublished - May 15 2018

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Cathepsins
Zinc Fingers
Ligases
Ubiquitin
Breast Neoplasms
Heterografts
Triple Negative Breast Neoplasms
Cathepsin L
Cathepsin B
Cell Line
Neoplasms
Carcinogenesis
Growth
Transcriptome
Breast
Transcription Factors
Down-Regulation
Survival
DNA
Enzymes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Loss of the nuclear pool of Ubiquitin ligase CHIP/STUB1 in breast cancer unleashes the MZF1-cathepsin pro-oncogenic program. / Luan, Haitao; Mohapatra, Bhopal; 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 M.; Meza, Jane L; Raja, Srikumar; Rakha, Emad A.; Band, Vimla; Band, Hamid.

In: Cancer Research, Vol. 78, No. 10, 15.05.2018, p. 2524-2535.

Research output: Contribution to journalArticle

Luan, H, Mohapatra, B, Bielecki, TA, Mushtaq, I, Mirza, S, Jennings, TA, Clubb, RJ, An, W, Ahmed, D, El-Ansari, R, Storck, MD, Mishra, NK, Guda, C, Sheinin, YM, Meza, JL, Raja, S, Rakha, EA, 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, vol. 78, no. 10, pp. 2524-2535. https://doi.org/10.1158/0008-5472.CAN-16-2140
Luan, Haitao ; Mohapatra, Bhopal ; 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 M. ; Meza, Jane L ; Raja, Srikumar ; Rakha, Emad A. ; Band, Vimla ; Band, Hamid. / Loss of the nuclear pool of Ubiquitin ligase CHIP/STUB1 in breast cancer unleashes the MZF1-cathepsin pro-oncogenic program. In: Cancer Research. 2018 ; Vol. 78, No. 10. pp. 2524-2535.
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AU - Mushtaq, Insha

AU - Mirza, Sameer

AU - Jennings, Tameka A.

AU - Clubb, Robert J.

AU - An, Wei

AU - Ahmed, Dena

AU - El-Ansari, Rokaya

AU - Storck, Matthew D.

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AU - Guda, Chittibabu

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