BackgroundHistone deacetylase inhibitors (HDACis) re-express silenced tumor suppressor genes and are currently undergoing clinical trials. Although HDACis have been known to induce gene expression, an equal number of genes are downregulated upon HDAC inhibition. The mechanism behind this downregulation remains unclear. Here we provide evidence that several DNA repair genes are downregulated by HDAC inhibition and provide a mechanism involving the E2F1 transcription factor in the process.Methodology/Principal FindingsApplying Analysis of Functional Annotation (AFA) on microarray data of prostate cancer cells treated with HDACis, we found a number of genes of the DNA damage response and repair pathways are downregulated by HDACis. AFA revealed enrichment of homologous recombination (HR) DNA repair genes of the BRCA1 pathway, as well as genes regulated by the E2F1 transcription factor. Prostate cancer cells demonstrated a decreased DNA repair capacity and an increased sensitization to chemical- and radio-DNA damaging agents upon HDAC inhibition. Recruitment of key HR repair proteins to the site of DNA damage, as well as HR repair capacity was compromised upon HDACi treatment. Based on our AFA data, we hypothesized that the E2F transcription factors may play a role in the downregulation of key repair genes upon HDAC inhibition in prostate cancer cells. ChIP analysis and luciferase assays reveal that the downregulation of key repair genes is mediated through decreased recruitment of the E2F1 transcription factor and not through active repression by repressive E2Fs.Conclusions/SignificanceOur study indicates that several genes in the DNA repair pathway are affected upon HDAC inhibition. Downregulation of the repair genes is on account of a decrease in amount and promoter recruitment of the E2F1 transcription factor. Since HDAC inhibition affects several pathways that could potentially have an impact on DNA repair, compromised DNA repair upon HDAC inhibition could also be attributed to several other pathways besides the ones investigated in this study. However, our study does provide insights into the mechanism that governs downregulation of HR DNA repair genes upon HDAC inhibition, which can lead to rationale usage of HDACis in the clinics.

Although uterine contractions in the non-pregnant uterus have been studied extensively, the knowledge gained has not been used in general fertility treatment work-up. In this review paper, we provide an overview of the current knowledge on uterine peristalsis (UP), based on the available literature. This literature shows that UP influences pregnancy chances in both natural and artificial cycles. Although the physiological background of these contractions is not completely clear, we know that several factors can be of influence, like uterine pathologies and hormones. Several options to alter pregnancy outcome by interfering with uterine contractions have been studied. Our meta-analysis on therapeutic options shows positive results of progesterone at time of embryo transfer in IVF cycles or prostaglandins at time of intrauterine insemination, although the quality of evidence is low. These therapies are probably most beneficial in selected groups of patients with abnormal contraction patterns. The introduction of an objective and user-friendly UP measuring tool suitable for use in daily practice would make it possible to identify and monitor these patients. We suggest that future research should focus on the physiology of initiation of UP and on the development of an effective standard measuring tool.

VPA may be functioning as an HDACI to inhibit growth of PCa cells in vitro and in vivo by modulating multiple pathways including cell cycle arrest, apoptosis, angiogenesis, and senescence.