Induction of USP17 by combining BET and HDAC inhibitors in breast cancer cells.

Abstract

Members of the bromodomain and extra-C terminal (BET) domain protein family and the histone deacetylase (HDAC) enzyme family regulate the expression of important oncogenes and tumor suppressor genes. Here we show that the BET inhibitor JQ1 inhibits proliferation and induces apoptosis of both triple negative and estrogen receptor positive breast cancer cells. Consistent with the critical role of histone acetylation in the regulation of gene expression, treatment with JQ1 or the HDAC inhibitor mocetinostat was associated with global changes in gene expression resulting in suppression of genes involved in cell-cycle regulation. Combining JQ1 with mocetinostat, further decreased cell viability. This synergistic effect was associated with increased suppression of genes essential for cell-cycle progression. Furthermore, we detected dramatic increase in the expression of several members of the ubiquitin-specific protease 17 (USP17) family of deubiquitinating enzymes in response to the combination treatment. Increased expression of USP17 enzymes were able to attenuate the Ras/MAPK pathway causing decrease in cell viability, while, siRNA mediated depletion of USP17 significantly decreased cytotoxicity after the combination treatment. In conclusion, our study demonstrates that co-treatment with BET inhibitors and HDAC inhibitors reduces breast cancer cell viability through induction of USP17.

• Authors: Gabor Borbely, Lars-Arne Haldosen, Karin Dahlman-Wright, Chunyan Zhao
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 32 Pg. 33623-35 (Oct 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26378038 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (+)-JQ1 compound
• Azepines
• BRD2 protein, human
• BRD3 protein, human
• BRD4 protein, human
• Benzamides
• Cell Cycle Proteins
• Histone Deacetylase Inhibitors
• Nuclear Proteins
• Pyrimidines
• RNA, Small Interfering
• RNA-Binding Proteins
• Transcription Factors
• Triazoles
• mocetinostat
• Protein Serine-Threonine Kinases
• Endopeptidases
• USP17L2 protein, human

Topics

• Azepines (pharmacology)
• Benzamides (pharmacology)
• Breast Neoplasms (drug therapy, enzymology, genetics)
• Cell Cycle Proteins
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Synergism
• Endopeptidases (biosynthesis, genetics, metabolism)
• Enzyme Induction (drug effects)
• Female
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• MAP Kinase Signaling System
• MCF-7 Cells
• Nuclear Proteins (antagonists & inhibitors)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Pyrimidines (pharmacology)
• RNA, Small Interfering (administration & dosage, genetics)
• RNA-Binding Proteins (antagonists & inhibitors)
• Transcription Factors (antagonists & inhibitors)
• Triazoles (pharmacology)
• Up-Regulation (drug effects)