Lemur tail kinase 3 serves as a predictor of patient outcomes and a target for the treatment of ovarian cancer.

Lemur tail kinase 3 (LMTK3) belongs to a family of tyrosine kinases that are known to correlate with tumor grade and patient survival in some cancers. Here, we validated LMTK3 as a specific target and a prognostic biomarker in ovarian cancer (OC). In samples from 204 stage I-II OC patients, immunohistochemical studies revealed a higher cytoplasmic-to-nuclear staining intensity of LMTK3, which correlated with worse overall survival ( < 0.

DNA Methylation Profiling of Human Hepatocarcinogenesis.

Background And Aims: Mutations in TERT (telomerase reverse transcriptase) promoter are established gatekeepers in early hepatocarcinogenesis, but little is known about other molecular alterations driving this process. Epigenetic deregulation is a critical event in early malignancies. Thus, we aimed to (1) analyze DNA methylation changes during the transition from preneoplastic lesions to early HCC (eHCC) and identify candidate epigenetic gatekeepers, and to (2) assess the prognostic potential of methylation changes in cirrhotic tissue.

High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells.

Metastatic uveal melanoma (UM) is a rare, but often lethal, form of ocular cancer arising from melanocytes within the uveal tract. UM has a high propensity to spread hematogenously to the liver, with up to 50% of patients developing liver metastases. Unfortunately, once liver metastasis occurs, patient prognosis is extremely poor with as few as 8% of patients surviving beyond two years.

IGF2 Is Up-regulated by Epigenetic Mechanisms in Hepatocellular Carcinomas and Is an Actionable Oncogene Product in Experimental Models.

Background & Aims: Effective treatments are urgently needed for hepatocellular carcinoma (HCC), which is usually diagnosed at advanced stages. Signaling via the insulin-like growth factor (IGF) pathway is aberrantly activated in HCC by IGF2 overexpression. We aimed to elucidate the mechanism of IGF2 overexpression and its oncogenic activities and evaluate the anti-tumor effects of reducing IGF2 signaling.

Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR.

Metastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade.

Head-to-head antisense transcription and R-loop formation promotes transcriptional activation.

The mechanisms used by antisense transcripts to regulate their corresponding sense mRNAs are not fully understood. Herein, we have addressed this issue for the vimentin (VIM) gene, a member of the intermediate filament family involved in cell and tissue integrity that is deregulated in different types of cancer. VIM mRNA levels are positively correlated with the expression of a previously uncharacterized head-to-head antisense transcript, both transcripts being silenced in colon primary tumors concomitant with promoter hypermethylation.

DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma.

Unlabelled: Epigenetic deregulation has emerged as a driver in human malignancies. There is no clear understanding of the epigenetic alterations in hepatocellular carcinoma (HCC) and of the potential role of DNA methylation markers as prognostic biomarkers. Analysis of tumor tissue from 304 patients with HCC treated with surgical resection allowed us to generate a methylation-based prognostic signature using a training-validation scheme.

Regulation of pri-miRNA processing by a long noncoding RNA transcribed from an ultraconserved region.

Noncoding RNAs (ncRNAs) control cellular programs by affecting protein-coding genes, but evidence increasingly points to their involvement in a network of ncRNA-ncRNA interactions. Here, we show that a long ncRNA, Uc.283+A, controls pri-miRNA processing.

Exploiting tumor vulnerabilities: epigenetics, cancer metabolism and the mTOR pathway in the era of personalized medicine.

Patient stratification according to drug responses, together with the discovery of novel antitumor targets, is leading to a new era of personalized cancer treatments. With the aim of identifying emerging pathways and the challenges faced by clinicians during clinical trials, the IDIBELL Cancer Conference on Personalized Cancer Medicine took place in Barcelona on December 3-4, 2012. This conference brought together speakers working in different areas of cancer research (epigenetics, metabolism and the mTOR pathway, cell death and the immune system, clinical oncology) to discuss the latest developments in personalized cancer medicine.

Intronic RNAs mediate EZH2 regulation of epigenetic targets.

Epigenetic deregulation at a number of genomic loci is one of the hallmarks of cancer. A role for some RNA molecules in guiding repressive polycomb complex PRC2 to specific chromatin regions has been proposed. Here we use an in vivo cross-linking method to detect and identify direct PRC2-RNA interactions in human cancer cells, revealing a number of intronic RNA sequences capable of binding to the core component EZH2 and regulating the transcriptional output of its genomic counterpart.

Bivalent histone modifications in stem cells poise miRNA loci for CpG island hypermethylation in human cancer.

It has been proposed that the existence of stem cell epigenetic patterns confer a greater likelihood of CpG island hypermethylation on tumor suppressor-coding genes in cancer. The suggested mechanism is based on the Polycomb-mediated methylation of K27 of histone H3 and the recruitment of DNA methyltransferases on the promoters of tumor suppressor genes in cancer cells, when those genes are preferentially pre-marked in embryonic stem cells (ESCs) with bivalent chromatin domains. On the other hand, miRNAs appear to be dysregulated in cancer, with many studies reporting silencing of miRNA genes due to aberrant hypermethylation of their promoter regions.

Regulation of SNAIL1 and E-cadherin function by DNMT1 in a DNA methylation-independent context.

Mammalian DNA methyltransferase 1 (DNMT1) is essential for maintaining DNA methylation patterns after cell division. Disruption of DNMT1 catalytic activity results in whole genome cytosine demethylation of CpG dinucleotides, promoting severe dysfunctions in somatic cells and during embryonic development. While these observations indicate that DNMT1-dependent DNA methylation is required for proper cell function, the possibility that DNMT1 has a role independent of its catalytic activity is a matter of controversy.

Epigenetic modifications and human disease.

Epigenetics is one of the most rapidly expanding fields in biology. The recent characterization of a human DNA methylome at single nucleotide resolution, the discovery of the CpG island shores, the finding of new histone variants and modifications, and the unveiling of genome-wide nucleosome positioning maps highlight the accelerating speed of discovery over the past two years. Increasing interest in epigenetics has been accompanied by technological breakthroughs that now make it possible to undertake large-scale epigenomic studies.

Molecular and bioinformatic analysis of the FB-NOF transposable element.

The Drosophila melanogaster transposable element FB-NOF is known to play a role in genome plasticity through the generation of all sort of genomic rearrangements. Moreover, several insertional mutants due to FB mobilizations have been reported. Its structure and sequence, however, have been poorly studied mainly as a consequence of the long, complex and repetitive sequence of FB inverted repeats.

An FB-NOF mediated duplication of the white gene is responsible for the zeste1 phenotype in some Drosophila melanogaster unstable strains.

The males of the Drosophila melanogaster M115 mutant strain and of its spontaneous revertant strain RM115 are phenotypically similar to those carrying the w(+UZ) and w(+UR) alleles. The molecular description of these mutant strains could be extended to the unstable-zeste system, which has been used as a genotoxicity test, and could be of use for a better understanding of the assay. An FB element in the 3' vicinity of the white gene, actually into the second intron of the newly predicted CG32795 gene, was found and precisely located in our M115 and RM115 strains, and also in w(+UZ) as expected.