Dynamic patterns of DNA methylation in the normal prostate epithelial differentiation program are targets of aberrant methylation in prostate cancer.

Understanding the epigenetic control of normal differentiation programs might yield principal information about critical regulatory states that are disturbed in cancer. We utilized the established non-malignant HPr1-AR prostate epithelial cell model that upon androgen exposure commits to a luminal cell differentiation trajectory from that of a basal-like state. We profile the dynamic transcriptome associated with this transition at multiple time points (0 h, 1 h, 24 h, 96 h), and confirm that expression patterns are strongly indicative of a progressive basal to luminal cell differentiation program based on human expression signatures.

Nuclear receptors in cancer - uncovering new and evolving roles through genomic analysis.

Nuclear receptors (NRs) have historically been at the forefront of cancer research, where they are known to act as critical regulators of disease. They also serve as biomarkers for tumour subclassification and targets for hormone therapy. However, most tumour types express extensive repertoires of NRs, whose interactions provide multiple paths for disease progression and offer potentially untapped mechanisms for therapeutic interventions.

Functional assessment of human enhancer activities using whole-genome STARR-sequencing.

Background: Genome-wide quantification of enhancer activity in the human genome has proven to be a challenging problem. Recent efforts have led to the development of powerful tools for enhancer quantification. However, because of genome size and complexity, these tools have yet to be applied to the whole human genome.

Hormone stimulation of androgen receptor mediates dynamic changes in DNA methylation patterns at regulatory elements.

DNA methylation is an epigenetic modification that contributes to stable gene silencing by interfering with the ability of transcriptional regulators to bind to DNA. Recent findings have revealed that hormone stimulation of certain nuclear receptors induces rapid, dynamic changes in DNA methylation patterns alongside transcriptional responses at a subset of target loci, over time. However, the ability of androgen receptor (AR) to dynamically regulate gene transcription is relatively under-studied and its role in the regulation of DNA methylation patterns remains to be elucidated.

KLLN epigenotype-phenotype associations in Cowden syndrome.

Germline KLLN promoter hypermethylation was recently identified as a potential genetic etiology of the cancer predisposition syndrome, Cowden syndrome (CS), when no causal PTEN gene mutation was found. We screened for KLLN promoter methylation in a large prospective series of CS patients and determined the risk of benign and malignant CS features in patients with increased methylation both with and without a PTEN mutation/variant of unknown significance. In all, 1012 CS patients meeting relaxed International Cowden Consortium criteria including 261 PTEN mutation-positive CS patients, 187 PTEN variant-positive CS patients and 564 PTEN mutation-negative CS patients, as well as 111 population controls were assessed for germline KLLN promoter methylation by MassARRAY EpiTYPER analysis.

Epigenetic distortion to VDR transcriptional regulation in prostate cancer cells.

The current study aimed to examine the gene specific mechanisms by which the actions of the vitamin D receptor (VDR) are distorted in prostate cancer. Transcriptional responses toward the VDR ligand, 1α,25(OH)2D3, were examined in non-malignant prostate epithelial cells (RWPE-1) and compared to the 1α,25(OH)2D3-recalcitrant prostate cancer cells (PC-3). Time resolved transcriptional studies for two VDR target genes revealed selective attenuation and repression of VDR transcriptional responses in PC-3 cells.

Recruitment of NCOR1 to VDR target genes is enhanced in prostate cancer cells and associates with altered DNA methylation patterns.

The current study investigated transcriptional distortion in prostate cancer cells using the vitamin D receptor (VDR) as a tool to examine how epigenetic events driven by corepressor binding and CpG methylation lead to aberrant gene expression. These relationships were investigated in the non-malignant RWPE-1 cells that were 1α,25(OH)(2)D(3) responsive (RWPE-1) and malignant cell lines that were 1α,25(OH)(2)D(3) partially responsive (RWPE-2) and resistant (PC-3). These studies revealed that selective attenuation and repression of VDR transcriptional responses in the cancer cell lines reflected their loss of antiproliferative sensitivity.

Dietary folate deficiency blocks prostate cancer progression in the TRAMP model.

Dietary folate is essential in all tissues to maintain several metabolite pools and cellular proliferation. Prostate cells, due to specific metabolic characteristics, have increased folate demand to support proliferation and prevent genetic and epigenetic damage. Although several studies have found that dietary folate interventions can affect colon cancer biology in rodent models, its impact on prostate is unknown.