Zhao, Weiye, Stenning, Jack, Bridge, Katherine S orcid.org/0000-0003-1516-1459 et al. (3 more authors) (2024) ZMIZ1 enhances ERα-dependent expression of E2F2 in breast cancer. Journal of molecular endocrinology. e230133. ISSN 0952-5041
Abstract
The estrogen receptor-α (ER) drives 75% of breast cancers. On activation, the ER recruits and assembles a 1–2 MDa transcriptionally active complex. These complexes can modulate tumour growth, and understanding the roles of individual proteins within these complexes can help identify new therapeutic targets. Here, we present the discovery of ER and ZMIZ1 within the same multi-protein assembly by quantitative proteomics, and validated by proximity ligation assay. We characterise ZMIZ1 function by demonstrating a significant decrease in the proliferation of ER-positive cancer cell lines. To establish a role for the ER-ZMIZ1 interaction, we measured the transcriptional changes in the estrogen response post-ZMIZ1 knockdown using an RNA-seq time-course over 24 h. Gene set enrichment analysis of the ZMIZ1-knockdown data identified a specific delay in the response of estradiol-induced cell cycle genes. Integration of ENCODE data with our RNA-seq results identified that ER and ZMIZ1 both bind the promoter of E2F2. We therefore propose that ER and ZMIZ1 interact to enable the efficient estrogenic response at subset of cell cycle genes via a novel ZMIZ1–ER–E2F2 signalling axis. Finally, we show that high ZMIZ1 expression is predictive of worse patient outcome, ER and ZMIZ1 are co-expressed in breast cancer patients in TCGA and METABRIC, and the proteins are co-localised within the nuclei of tumour cell in patient biopsies. In conclusion, we establish that ZMIZ1 is a regulator of the estrogenic cell cycle response and provide evidence of the biological importance of the ER–ZMIZ1 interaction in ER-positive patient tumours, supporting potential clinical relevance.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 the author(s) |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) The University of York > Faculty of Sciences (York) > Chemistry (York) |
Funding Information: | Funder Grant number BBSRC (BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL) BB/V000071/1 THE ROYAL SOCIETY RGS\R2\202120 |
Depositing User: | Pure (York) |
Date Deposited: | 29 Apr 2024 14:20 |
Last Modified: | 22 Mar 2025 00:12 |
Published Version: | https://doi.org/10.1530/JME-23-0133 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1530/JME-23-0133 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:212086 |