Targeting of H19/cell adhesion molecules circuitry by GSK-J4 epidrug inhibits metastatic progression in prostate cancer.

Background: About 30% of Prostate cancer (PCa) patients progress to metastatic PCa that remains largely incurable. This evidence underlines the need for the development of innovative therapies. In this direction, the potential research focus might be on long non-coding RNAs (lncRNAs) like H19, which serve critical biological functions and show significant dysregulation in cancer.

MALAT1 as a Regulator of the Androgen-Dependent Choline Kinase A Gene in the Metabolic Rewiring of Prostate Cancer.

Background: Choline kinase alpha (CHKA), an essential gene in phospholipid metabolism, is among the modulated MALAT1-targeted transcripts in advanced and metastatic prostate cancer (PCa).

Methods: We analyzed CHKA mRNA by qPCR upon MALAT1 targeting in PCa cells, which is characterized by high dose-responsiveness to the androgen receptor (AR) and its variants. Metabolome analysis of MALAT1-depleted cells was performed by quantitative High-resolution 1 H-Nuclear Magnetic Resonance (NMR) spectroscopy.

Diagnostic and prognostic potential of the proteomic profiling of serum-derived extracellular vesicles in prostate cancer.

Extracellular vesicles (EVs) and their cargo represent an intriguing source of cancer biomarkers for developing robust and sensitive molecular tests by liquid biopsy. Prostate cancer (PCa) is still one of the most frequent and deadly tumor in men and analysis of EVs from biological fluids of PCa patients has proven the feasibility and the unprecedented potential of such an approach. Here, we exploited an antibody-based proteomic technology, i.

Metabolic Reprogramming by Malat1 Depletion in Prostate Cancer.

The lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes growth and progression in prostate cancer (PCa); however, little is known about its possible impact in PCa metabolism. The aim of this work has been the assessment of the metabolic reprogramming associated with MALAT1 silencing in human PCa cells and in an ex vivo model of organotypic slice cultures (OSCs). Cultured cells and OSCs derived from primary tumors were transfected with MALAT1 specific gapmers.

Signaling through estrogen receptors modulates long non-coding RNAs in prostate cancer.

Prostate cancer (PCa) is a sex-steroid hormone-dependent cancer in which estrogens play a critical role in both initiation and progression. Recently, several long non-coding RNAs (lncRNAs) have been associated with PCa and are supposedly playing a pivotal role in the biology and progression of this type of cancer. In this review, we focused on some lncRNAs that are known for their androgen and estrogen transcriptional responsiveness in PCa.

H19-Dependent Transcriptional Regulation of β3 and β4 Integrins Upon Estrogen and Hypoxia Favors Metastatic Potential in Prostate Cancer.

Estrogen and hypoxia promote an aggressive phenotype in prostate cancer (PCa), driving transcription of progression-associated genes. Here, we molecularly dissect the contribution of long non-coding RNA H19 to PCa metastatic potential under combined stimuli, a topic largely uncovered. The effects of estrogen and hypoxia on H19 and cell adhesion molecules' expression were investigated in PCa cells and PCa-derived organotypic slice cultures (OSCs) by qPCR and Western blot.

Nucleoporin 153 regulates estrogen-dependent nuclear translocation of endothelial nitric oxide synthase and estrogen receptor beta in prostate cancer.

Nucleoporin 153 (Nup153), key regulator of nuclear import/export, has been recently associated to oncogenic properties in pancreatic and breast tumour cells modulating either cell motility and migration or gene expression by chromatin association. In the present work, we have characterized the role of Nup153 in a cellular model of prostate cancer (PCa). The analysis of several immortalized cell lines derived from freshly explants of prostate cancer specimens showed that Nup153 protein was higher and present in multimeric complexes with eNOS and ERβ as compared to normal/hyperplastic prostate epithelial cells.

Establishment of a protocol to extend the lifespan of human hormone-secreting pituitary adenoma cells.

Purpose: The aim of this study was to generate immortalized human anterior pituitary adenoma cells. Reliable cell models for the study of human pituitary adenomas are as yet lacking and studies performed so far used repeated passaging of freshly excised adenomas, with the attendant limitations due to limited survival in culture, early senescence, and poor reproducibility.

Methods & Results: We devised a technique based upon repeated co-transfections of two retroviral vectors, one carrying the catalytic subunit of human telomerase, hTERT, the other SV40 large T antigen.

Transcription Factor CREM Mediates High Glucose Response in Cardiomyocytes and in a Male Mouse Model of Prolonged Hyperglycemia.

This study aims at investigating the epigenetic landscape of cardiomyocytes exposed to elevated glucose levels. High glucose (30 mM) for 72 hours determined some epigenetic changes in mouse HL-1 and rat differentiated H9C2 cardiomyocytes including upregulation of class I and III histone deacetylase protein levels and activity, inhibition of histone acetylase p300 activity, increase in histone H3 lysine 27 trimethylation, and reduction in H3 lysine 9 acetylation. Gene expression analysis focused on cardiotoxicity revealed that high glucose induced markers associated with tissue damage, fibrosis, and cardiac remodeling such as Nexilin (NEXN), versican, cyclic adenosine 5'-monophosphate-responsive element modulator (CREM), and adrenoceptor α2A (ADRA2).

MALAT1 and HOTAIR Long Non-Coding RNAs Play Opposite Role in Estrogen-Mediated Transcriptional Regulation in Prostate Cancer Cells.

In the complex network of nuclear hormone receptors, the long non-coding RNAs (lncRNAs) are emerging as critical determinants of hormone action. Here we investigated the involvement of selected cancer-associated lncRNAs in Estrogen Receptor (ER) signaling. Prior studies by Chromatin Immunoprecipitation (ChIP) Sequencing showed that in prostate cancer cells ERs form a complex with the endothelial nitric oxide synthase (eNOS) and that in turn these complexes associate with chromatin in an estrogen-dependent fashion.

Anacardic acid and thyroid hormone enhance cardiomyocytes production from undifferentiated mouse ES cells along functionally distinct pathways.

The epigenetics of early commitment to embryonal cardiomyocyte is poorly understood. In this work, we compared the effect of thyroid hormone and that of anacardic acid, a naturally occurring histone acetylase inhibitor, or both in combination, on mouse embryonic stem cells (mES) differentiating into embryonal cardiomyocyte by embryoid bodies (EBs) formation. Although the results indicated that anacardic acid (AA) and thyroid hormone were both efficient in promoting cardiomyocyte differentiation, we noticed that a transient exposure of mES to AA alone was sufficient to enlarge the beating areas of EBs compared to those of untreated controls.

A basal level of DNA damage and telomere deprotection increases the sensitivity of cancer cells to G-quadruplex interactive compounds.

Here, with the aim of obtaining insight into the intriguing selectivity of G-quadruplex (G4) ligands toward cancer compared to normal cells, a genetically controlled system of progressive transformation in human BJ fibroblasts was analyzed. Among the different comparative evaluations, we found a progressive increase of DNA damage response (DDR) markers throughout the genome from normal toward immortalized and transformed cells. More interestingly, sensitivity to G4 ligands strongly correlated with the presence of a basal level of DNA damage, including at the telomeres, where the chromosome ends were exposed to the DDR without concurrent induction of DNA repair activity, as revealed by the lack of 53BP1 recruitment and telomere aberrations.

Estrogen-dependent dynamic profile of eNOS-DNA associations in prostate cancer.

In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERβ) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1.

HIPK2 downregulates vimentin and inhibits breast cancer cell invasion.

Vimentin, a mesenchymal marker, is frequently overexpressed in epithelial carcinomas undergoing epithelial to mesenchymal transition (EMT), a condition correlated with invasiveness and poor prognosis. Therefore, vimentin is a potential molecular target for anticancer therapy. Emerging studies in experimental models underscore the functions of homeodomain-interacting protein kinase 2 (HIPK2) as potential oncosuppressor by acting as transcriptional corepressor or catalytic activator of molecules involved in apoptosis and response to antitumor drugs.

The role of nuclear endothelial nitric oxide synthase in the endothelial and prostate microenvironments.

This review is based on novel observations from our laboratory on the nuclear translocation and functional role of endothelial nitric oxide synthase (eNOS) in endothelial and prostate cancer (PCa) epithelial cells. Nitric oxide (NO), the product of eNOS, is a free radical involved in the physiology and pathophysiology of living organisms and in a variety of biological processes including the maintenance of vascular homeostasis. Of relevance in this context is the role that estrogens play in the apoptotic process and the migration of endothelial cells through the regulation of target genes such as eNOS itself.

Zinc downregulates HIF-1α and inhibits its activity in tumor cells in vitro and in vivo.

Background: Hypoxia inducible factor-1α (HIF-1α) is responsible for the majority of HIF-1-induced gene expression changes under hypoxia and for the "angiogenic switch" during tumor progression. HIF-1α is often upregulated in tumors leading to more aggressive tumor growth and chemoresistance, therefore representing an important target for antitumor intervention. We previously reported that zinc downregulated HIF-1α levels.

HMGA1 protein is a positive regulator of the insulin-like growth factor-I receptor gene.

The IGF-I receptor (IGF-IR) is often overexpressed in cancer and is believed to play a crucial role in cancer progression. High Mobility Group A1 (HMGA1) is a non-histone chromatin protein that has the ability to regulate gene expression through DNA binding and involvement in enhanceosome complexes. HMGA1 is expressed at low level in adult differentiated cells, whereas it is expressed at high level in embryonic and malignant cells.

Endothelial NOS, estrogen receptor beta, and HIFs cooperate in the activation of a prognostic transcriptional pattern in aggressive human prostate cancer.

The identification of biomarkers that distinguish between aggressive and indolent forms of prostate cancer (PCa) is crucial for diagnosis and treatment. In this study, we used cultured cells derived from prostate tissue from patients with PCa to define a molecular mechanism underlying the most aggressive form of PCa that involves the functional activation of eNOS and HIFs in association with estrogen receptor beta (ERbeta). Cells from patients with poor prognosis exhibited a constitutively hypoxic phenotype and increased NO production.

Estrogen receptor-alpha and endothelial nitric oxide synthase nuclear complex regulates transcription of human telomerase.

We report that in endothelial cells, the angiogenic effect of 17beta-estradiol (E2) is inhibited by the estrogen receptor (ER) antagonist ICI or the NO synthase (NOS) inhibitor 7-nitroindazole via downregulation of hTERT, the telomerase catalytic subunit, suggesting that E2 and NO are involved in controlling hTERT transcription. Quantitative Real-Time PCR and chromatin immunoprecipitations in E2-treated human umbilical vein endothelial cells, showed recruitment of ERs on the hTERT promoter and concomitant enrichment in histone 3 methylation at Lysine 79, a modification associated with transcription-competent chromatin. Confocal microscopy and re-chromatin immunoprecipitations revealed that on E2 induction, endothelial (e)NOS rapidly localized into the nucleus and associated with ERalpha on the hTERT promoter.

SSADH variation in primates: intra- and interspecific data on a gene with a potential role in human cognitive functions.

In the present study we focus on the nucleotide and the inferred amino acid variation occurring in humans and other primate species for mitochondrial NAD(+)-dependent succinic semialdehyde dehydrogenase, a gene recently supposed to contribute to cognitive performance in humans. We determined 2527 bp of coding, intronic, and flanking sequences from chimpanzee, bonobo, gorilla, orangutan, gibbon, and macaque. We also resequenced the entire coding sequence on 39 independent chromosomes from Italian families.

Peroxisomal proliferator-activated receptor-gamma agonists induce partial reversion of epithelial-mesenchymal transition in anaplastic thyroid cancer cells.

Anaplastic thyroid cancer (ATC) is an extremely aggressive tumor characterized by marked epithelial mesenchymal transition, which leads, almost invariably, to death. Peroxisomal proliferator-activated receptor (PPAR)-gamma agonists have recently emerged as potential antineoplastic drugs. To establish whether ATC could be a target of PPAR gamma agonists, we first examined PPAR gamma protein expression in a panel of six ATC cell lines and then studied the biologic effects of two PPAR gamma agonists, ciglitazone and rosiglitazone, that belong to the class of thiazolidonediones.