Induction of USP17 by combining BET and HDAC inhibitors in breast cancer cells
Metrics: PDF 2653 views | HTML 2340 views | ?
Gabor Borbely1,3, Lars-Arne Haldosen1, Karin Dahlman-Wright1,2 and Chunyan Zhao1
1 Karolinska Institutet, Department of Biosciences and Nutrition, Novum, Huddinge, Sweden
2 SciLifeLab, Karolinska Institutet, Solna, Sweden
3 Current address: Swetox & Karolinska Institutet, Unit for Toxicology Sciences, Södertälje, Sweden
Gabor Borbely, email:
Chunyan Zhao, email:
Keywords: breast cancer, epigenetics, BET, HDAC, combined treatment
Received: March 27, 2015 Accepted: August 26, 2015 Published: September 10, 2015
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.