BAY 1024767 blocks androgen receptor mutants found in castration-resistant prostate cancer patients.

Androgen receptor (AR) mutations arise in patients developing resistance to hormone deprivation therapies. Here we describe BAY 1024767, a thiohydantoin derivative with strong antagonistic activity against nine AR variants with mutations located in the AR ligand-binding domain (LBD), and against wild-type AR. Antagonism was maintained, though reduced, at increased androgen levels.

Efficacy of MS-275, a selective inhibitor of class I histone deacetylases, in human colon cancer models.

N-(2-aminophenyl)-4-[N-(pyridine-3yl-methoxy-carbonyl) aminomethyl] benzamide (MS-275) is a second generation histone deacetylase (HDAC) inhibitor with significant anti-tumor efficacy currently in clinical development. We investigated the effect of MS-275 treatment on various colon cancer cell lines, as well as on mouse xenograft models derived from human colorectal cancer. MS-275 exerted strong anti-proliferative effects in five cell lines and increased the acetylation of histones 3 and 4.

Androgen receptor acetylation sites differentially regulate gene control.

Androgen receptor (AR) function is modulated by post-translational modifications such as acetylation, ubiquitylation, sumoylation, and phosphorylation. Concerning acetylation, three lysines residues located in a consensus KxKK motif of the AR hinge domain have been identified. For a better evaluation of the role of this modification, the activity of AR modified at different acetylation sites was determined by comparing the effects on natural and synthetic promoters.

Phylogenetic conservation of the androgen receptor AR45 variant form in placental mammals.

A cDNA coding for a tissue-specific AR45 variant form of the androgen receptor (AR) has recently been identified in humans, with highest expression levels found in heart. The deduced protein comprises the DNA-binding domain, hinge region and ligand-binding domain of the AR, but not the N-terminal domain which is replaced by a unique, short, seven amino-acid-long stretch. This sequence is encoded by the mutually exclusive exon 1B, located between exons 1 and 2 of the human AR gene.

The ubiquitin-specific protease USP10 modulates androgen receptor function.

The role of the ubiquitin/proteasome system in degrading nuclear hormone receptors and regulating their transcriptional function has emerged in the last few years. We identified the ubiquitin-specific protease USP10 as part of DNA-bound androgen receptor (AR) complexes purified from nuclear extracts of PC-3 cells stably expressing the AR. The interaction between USP10 and the AR was confirmed by GST pull-down assays.