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Estrogen-dependent gene transcription in human breast cancer cells relies upon proteasome-dependent monoubiquitination of histone H2B

Prenzel, Tanja, Begus-Nahrmann, Yvonne, Kramer, Frank, Hennion, Magali, Hsu, Chieh, Gorsler, Theresa, Hintermair, Corinna, Eick, Dirk, Kremmer, Elisabeth, Simons, Mikael, and others. (2011) Estrogen-dependent gene transcription in human breast cancer cells relies upon proteasome-dependent monoubiquitination of histone H2B. Cancer Research, 71 (17). pp. 5739-5753. ISSN 1538-7445. (doi:10.1158/0008-5472.CAN-11-1896) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided. (Contact us about this Publication)
Official URL
http://dx.doi.org/10.1158/0008-5472.CAN-11-1896

Abstract

The estrogen receptor-? (ER?) determines the phenotype of breast cancers where it serves as a positive prognostic indicator. ER? is a well-established target for breast cancer therapy, but strategies to target its function remain of interest to address therapeutic resistance and further improve treatment. Recent findings indicate that proteasome inhibition can regulate estrogen-induced transcription, but how ER? function might be regulated was uncertain. In this study, we investigated the transcriptome-wide effects of the proteasome inhibitor bortezomib on estrogen-regulated transcription in MCF7 human breast cancer cells and showed that bortezomib caused a specific global decrease in estrogen-induced gene expression. This effect was specific because gene expression induced by the glucocorticoid receptor was unaffected by bortezomib. Surprisingly, we observed no changes in ER? recruitment or assembly of its transcriptional activation complex on ER? target genes. Instead, we found that proteasome inhibition caused a global decrease in histone H2B monoubiquitination (H2Bub1), leading to transcriptional elongation defects on estrogen target genes and to decreased chromatin dynamics overall. In confirming the functional significance of this link, we showed that RNA interference-mediated knockdown of the H2B ubiquitin ligase RNF40 decreased ER?-induced gene transcription. Surprisingly, RNF40 knockdown also supported estrogen-independent cell proliferation and activation of cell survival signaling pathways. Most importantly, we found that H2Bub1 levels decrease during tumor progression. H2Bub1 was abundant in normal mammary epithelium and benign breast tumors but absent in most malignant and metastatic breast cancers. Taken together, our findings show how ER? activity is blunted by bortezomib treatment as a result of reducing the downstream ubiquitin-dependent function of H2Bub1. In supporting a tumor suppressor role for H2Bub1 in breast cancer, our findings offer a rational basis to pursue H2Bub1-based therapies for future management of breast cancer.

Item Type: Article
DOI/Identification number: 10.1158/0008-5472.CAN-11-1896
Subjects: Q Science > QH Natural history > QH301 Biology
R Medicine
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Chieh Hsu
Date Deposited: 16 Mar 2015 11:55 UTC
Last Modified: 02 Jul 2019 08:37 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/47682 (The current URI for this page, for reference purposes)
Hsu, Chieh: https://orcid.org/0000-0002-4780-1222
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