Abstract
The estrogen receptor-α (ERα) determines the phenotype of breast cancers where it serves as a positive prognostic indicator. ERα 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 ERα 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 ERα recruitment or assembly of its transcriptional activation complex on ERα 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 ERα-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 ERα 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.
Highlights
The estrogen receptor-a (ERa) is a ligand-activated transcription factor which plays an essential role in a numberAuthors' Affiliations: 1Department of Molecular Oncology, Go€ttingen Center for Molecular Biosciences, Departments of 2Medical Statistics and 3Neurology, University Medical Center Go€ttingen; 4Max-Planck-Institute for Experimental Medicine, Go€ttingen; 5Department of Molecular Epigenetics, Helmholtz Center for Environmental Health and Center of Integrated Protein Science Munich (CIPSM); and 6Institute of Molecular Immunology, Helmholtz Center for Environmental Health, Munich, GermanyNote: Supplementary data for this article are available at Cancer Research Online.Y
We provide evidence that bortezomib blocks estrogen-induced gene transcription by a unique posttranscriptional initiation mechanism involving a loss of histone H2B monoubiquitination (H2Bub1) and changes in chromatin dynamics
To investigate the effects of a clinically utilized proteasome inhibitor on ERa activity, we validated the ability of bortezomib to block proteasome activity and determined the optimal concentration of bortezomib for blocking proteasome activity in ERa-positive MCF7 breast cancer cells
Summary
The estrogen receptor-a (ERa) is a ligand-activated transcription factor which plays an essential role in a numberAuthors' Affiliations: 1Department of Molecular Oncology, Go€ttingen Center for Molecular Biosciences, Departments of 2Medical Statistics and 3Neurology, University Medical Center Go€ttingen; 4Max-Planck-Institute for Experimental Medicine, Go€ttingen; 5Department of Molecular Epigenetics, Helmholtz Center for Environmental Health and Center of Integrated Protein Science Munich (CIPSM); and 6Institute of Molecular Immunology, Helmholtz Center for Environmental Health, Munich, GermanyNote: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).Y.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
