Abstract
Uveal melanoma (UM) is an aggressive intraocular malignancy with limited therapeutic options. Both primary and metastatic UM are characterized by oncogenic mutations in the G-protein alpha subunit q and 11. Furthermore, nearly 40% of UM has amplification of the chromosomal arm 8q and monosomy of chromosome 3, with consequent anomalies of MYC copy number. Chromatin regulators have become attractive targets for cancer therapy. In particular, the bromodomain and extra-terminal (BET) inhibitor JQ1 has shown selective inhibition of c-Myc expression with antiproliferative activity in hematopoietic and solid tumors. Here we provide evidence that JQ1 had cytotoxic activity in UM cell lines carrying Gnaq/11 mutations, while in cells without the mutations had little effects. Using microarray analysis, we identified a large subset of genes modulated by JQ1 involved in the regulation of cell cycle, apoptosis and DNA repair. Further analysis of selected genes determined that the concomitant silencing of Bcl-xL and Rad51 represented the minimal requirement to mimic the apoptotic effects of JQ1 in the mutant cells, independently of c-Myc. In addition, administration of JQ1 to mouse xenograft models of Gnaq-mutant UM resulted in significant inhibition of tumor growth.Collectively, our results define BRD4 targeting as a novel therapeutic intervention against UM with Gnaq/Gna11 mutations.
Highlights
Aberrant epigenetic regulation plays a central role into the genesis of cancer [1]
Silencing of the indicated genes (Figure 5C) did not induce inhibition of viability (Figure 5D), and the concomitant suppression of Bcl-xL and Rad51 had partial effects that were not statistically significant. These results suggest that genes like Rad51 and Bcl-xL regulate Uveal melanoma (UM) cell survival, while in melanoma cells JQ1-induced apoptosis seems to be mediated by other mechanisms [32]
Using chromatin immunoprecipitation assay (ChIP), we found that BRD4 was enriched at the Bcl-xL promoter in the Gnaq-mutant cells (Figure 6C), and the treatment with JQ1 diminished this binding
Summary
Aberrant epigenetic regulation plays a central role into the genesis of cancer [1]. BET inhibitors are emerging therapeutics in oncology that disrupt the interaction between BET proteins and chromatin, resulting in the inhibition of cancer growth [2, 3]. The BET family of proteins, including BRD2, BRD3, BRD4, and BRDT are chromatin readers containing two tandem aminoterminal bromodomains that bind to acetylated lysine residues on histone tails. They direct the assembly of nuclear macromolecular complexes that regulate key biologic processes, including DNA replication, chromatin remodeling and transcription [2, 4]. Bromodomain targeting in cutaneous melanoma inhibited the expression of several BRD4-regulated genes, including c-Myc, SKP2 and ERK1 [14] These studies demonstrated that BET inhibitors influence predominantly the MYC transcriptome, other genes undergo expressional changes and simultaneously contributed to the decrease of cell viability
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