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

ABSTRACT: Members of bromodomain and extra-C terminal (BET) domain family and the histone deacetylase (HDAC) enzyme family efficiently regulate the expression of important oncogenes and tumor suppressors. HDACs induce histone hypoacetylation meanwhile BET proteins bind to acetylated lysines on histones to regulate gene transcription. Here we show that the BET inhibitor JQ1 inhibited proliferation and induced 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, microarray analysis revealed broad transcriptional changes after JQ1 or HDAC inhibitor treatment. By examining the molecular pathways affected by the epigenetic inhibitors we found that both BET and HDAC inhibitors are suppressing similar genes that were involved in cell cycle regulation. Combining JQ1 with HDAC inhibitors, we found that the combination significantly decreased cell viability. This effect was partly mediated by the more efficient suppression of genes essential for cell-cycle progression. Furthermore, we detected a dramatic increase in the expression of several members of the USP17 family of deubiquitinating enzymes in response to the single agent treatment, which further increased by the combination treatment. Since constitutive expression of USP17 has been reported to block the Ras/MAPK pathway, our data also suggest that the blockade of the Ras/MAPK pathway might also be involved in the synergistic effect of the combination treatment. In conclusion, this study suggests that co-treatment with BET inhibitors and HDAC inhibitors could be an effective treatment regime in future breast cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE65495 | GEO | 2015/09/30

SECONDARY ACCESSION(S): PRJNA274220

REPOSITORIES: GEO

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Project description:Selective bromodomains inhibitors block the interaction between diverse bromodomains and extraterminal domains (BET) proteins and acetylated proteins. These inhibitors have shown beneficial effects in cancers malignancies and experimental inflammation in mouse models, but data on renal diseases are scarce. We have investigated the effect of the BET proteins inhibitor JQ1 in a mice model of unilateral ureteral obstruction. Treatment with JQ1 diminished renal damage, the presence of inflammatory cell infiltration and the upregulation of proinflammatory genes. The in vitro evaluation of JQ1 on TNF-Î± inducible genes in renal cells showed that BET inhibition modulated several biological processes, including inflammation or immune response. Moreover, gene-silencing experiments showed that BRD4 regulates several proinflammatory genes (IL-6, CCL-2 and CCL-5) and chromatin immunoprecipitation techniques demonstrated that BRD4 specifically binds to acetylated histone H3 in the promoter region of those genes. The nuclear factor-ï«B (NF-ï«B) pathway regulates renal inflammation. The RelA NF-ï«B subunit is activated by acetylation of lysine 310. In damaged kidneys and in TNF-Î±-treated renal cells, JQ1 blocked the nuclear translocation of RelA/NF-ï«B and NF-ï«B-mediated gene expression. Additionally, obstructed kidneys showed an activation of the Th17 immune response, which was diminished by JQ1 treatment. Our results demonstrate that the BET inhibition decreases renal inflammation by 3 independent mechanisms: 1) chromatin remodelling in the promoter regions of specific genes, 2) blocking NF-ï«B pathway activation, and 3) modulating the Th17 immune response. These results suggest that BET inhibitors could have important therapeutic applications in inflammatory renal diseases. HK2 cell line was treated with JQ1 or its enantiomer JQ1(-) (500nM) for 1 hour before stimulation or not with TNF-Î± (5ng/ml) for additional 3h. We analized the genes up- and down-regulated by TNF-Î± vs unstimulated cells, and further the genes downregulated or unaffected by JQ1 compared to the cells treated with the enantiomer (-) JQ1.

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

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