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.

Functional Impact of Chromatin Remodeling Gene Mutations and Predictive Signature for Therapeutic Response in Bladder Cancer

“…We therefore evaluated whether our HAT inactivation signature was inversely associated with mocetinostat treatment, as such a relationship would support further exploration of the HAT inactivation signature as a candidate biomarker for identifying likely responders to this treatment. In an analysis of gene expression profiles of MDA-MB-231 breast cancer cells treated with mocetinostat (26), we found that HAT inactivation scores decrease following treatment (Fig. 5D; P = 0.053), consistent with mocetinostat counteracting the effects of lost p300/CBP HAT activity.…”

Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises

“…In the majority of the studies, co-treatment of an HDAC inhibitor with another compound induced the inhibition of tumor growth and showed anti-proliferative effects (46,47,77,84,115,123,138,154). Also, several HDAC inhibitors are assosiated not only with autophagic cell death, but also apoptosis (44,55,70,71,84,97,153). Interestingly, many studies have found that HDAC inhibitors have the ability to convert ER-negative tumors to ER-positive tumors (111,160,161).…”

“…In other words, USP17 enzymes attenuated the Ras/MAPK pathway and cell viability was suppressed. On the other hand siRNA-mediated depletion of USP17, decreased the cytoxicity, indicating that the Ras/MAPK signaling pathway is involved in the synergistic effect of the combinational treatment (97). All these data show that the combination of HDAC and BET inhibitors could be used as potential therapeutic strategy for BC, given that it reduces the viability of TNBC cells, through induction of USP17.…”

“…Borbely et al studied the combination of mocetinostat and JQ1 in MDA-MB-231, BT549, MCF-7 and T47-D cells (97). JQ1 is a bromodomain and extra-C terminal (BET) inhibitor and is reported to participate in the expression of oncogenes and tumor suppressor genes.…”

“…Furthermore, combination treatment was associated with a sharp increase in the expression of many members of the ubiquitin-specific protease 17 (USP17) family of deubiquitinating enzymes (97). Previous studies have reported that USP17 regulates Ras/MAPK signaling partly through the regulation of the RCE1 (101).…”