This article is a US Government work and, as such, is in the public domain in the United States of America.
Genome wide transcriptional profiling in breast cancer cells reveals distinct changes in hormone receptor target genes and chromatin modifying enzymes after proteasome inhibition†
Article first published online: 31 MAR 2008
Published 2008 Wiley-Liss, Inc.
Volume 47, Issue 11, pages 845–885, November 2008
How to Cite
Kinyamu, H. K., Collins, J. B., Grissom, S. F., Hebbar, P. B. and Archer, T. K. (2008), Genome wide transcriptional profiling in breast cancer cells reveals distinct changes in hormone receptor target genes and chromatin modifying enzymes after proteasome inhibition. Mol. Carcinog., 47: 845–885. doi: 10.1002/mc.20440
- Issue published online: 24 OCT 2008
- Article first published online: 31 MAR 2008
- Manuscript Accepted: 18 FEB 2008
- Manuscript Revised: 3 FEB 2008
- Manuscript Received: 9 NOV 2007
- proteasome inhibitor;
- gene expression profiling;
- microarray analysis
Steroid hormone receptors, like glucocorticoid (GR) and estrogen receptors (ER), are master regulators of genes that control many biological processes implicated in health and disease. Gene expression is dependent on receptor levels which are tightly regulated by the ubiquitin-proteasome system. Previous studies have shown that proteasome inhibition increases GR, but decreases ER-mediated gene expression. At the gene expression level this divergent role of the proteasome in receptor-dependent transcriptional regulation is not well understood. We have used a genomic approach to examine the impact of proteasome activity on GR- and ER-mediated gene expression in MCF-7 breast cancer cells treated with dexamethasone (DEX) or 17β-estradiol (E2), the proteasome inhibitor MG132 (MG) or MG132 and either hormone (MD or ME2) for 24 h. Transcript profiling reveals that inhibiting proteasome activity modulates gene expression by GR and ER in a similar manner in that several GR and ER target genes are upregulated and downregulated after proteasome inhibition. In addition, proteasome inhibition modulates receptor-dependent genes involved in the etiology of a number of human pathological states, including multiple myeloma, leukemia, breast/prostate cancer, HIV/AIDS, and neurodegenerative disorders. Importantly, our analysis reveals that a number of transcripts encoding histone and DNA modifying enzymes, prominently histone/DNA methyltransferases and demethylases, are altered after proteasome inhibition. As proteasome inhibitors are currently in clinical trials as therapy for multiple myeloma, HIV/AIDS and leukemia, the possibility that some of the target molecules are hormone regulated and chromatin modifying enzymes is intriguing in this era of epigenetic therapy. Published 2008 Wiley-Liss, Inc.