• eccrine porocarcinoma
• skin cancer
• sweat gland carcinoma
• transcriptome analysis

• Humans
• Gene Expression Profiling
• Eccrine Porocarcinoma/genetics
• Eccrine Porocarcinoma/pathology
• Sweat Gland Neoplasms/genetics
• Sweat Gland Neoplasms/pathology
• Sweat Gland Neoplasms/metabolism
• Precancerous Conditions/genetics
• Precancerous Conditions/pathology
• Female
• Male
• Cell Transformation, Neoplastic/genetics
• Gene Expression Regulation, Neoplastic
• Aged
• Middle Aged

• Schweißdrüsenkarzinom
• Transkriptomanalysen
• eccrine porocarcinoma
• ekkrines Porokarzinom
• molekulare Profilierung
• skin cancer
• sweat gland carcinoma
• transcriptome analysis

• Humans
• Eccrine Porocarcinoma/genetics
• Eccrine Porocarcinoma/pathology
• Sweat Gland Neoplasms/genetics
• Sweat Gland Neoplasms/pathology
• Gene Expression Profiling
• Transcriptome/genetics
• Precancerous Conditions/genetics
• Precancerous Conditions/pathology
• Female
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/pathology
• Male
• Gene Expression Regulation, Neoplastic
• Middle Aged

• Biomarker
• Cell-free DNA
• Epigenetic
• Methylation
• Pancreatic cancer

Silencing of tumor suppressor genes (TSGs) through epigenetic mechanisms, mainly via abnormal promoter DNA methylation, is considered a main mechanism of tumorigenesis. The abnormal DNA methylation profiles are transmitted from the cancer mother cell to the daughter cells through the involvement of a macromolecular complex in which the ubiquitin-like containing plant homeodomain (PHD), and an interesting new gene (RING) finger domains 1 (UHRF1), play the role of conductor. Indeed, UHRF1 interacts with epigenetic writers, such as DNA methyltransferase 1 (DNMT1), histone methyltransferase G9a, erasers like histone deacetylase 1 (HDAC1), and functions as a hub protein. Thus, targeting UHRF1 and/or its partners is a promising strategy for epigenetic cancer therapy. The natural compound thymoquinone (TQ) exhibits anticancer activities by targeting several cellular signaling pathways, including those involving UHRF1. In this review, we highlight TQ as a potential multitarget single epidrug that functions by targeting the UHRF1/DNMT1/HDAC1/G9a complex. We also speculate on the possibility that TQ might specifically target UHRF1, with subsequent regulatory effects on other partners.

• UHRF1
• cancer
• epigenetic drug
• thymoquinone
• tumor suppressor gene

• Benzoquinones/pharmacology
• CCAAT-Enhancer-Binding Proteins/antagonists & inhibitors
• Carcinogenesis/drug effects
• Carcinogenesis/metabolism
• DNA (Cytosine-5-)-Methyltransferase 1/metabolism
• DNA Methylation/drug effects
• Epigenesis, Genetic/drug effects
• Humans
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Promoter Regions, Genetic/drug effects
• Signal Transduction/drug effects
• Ubiquitin-Protein Ligases/antagonists & inhibitors

Pancreatic adenocarcinoma has a horrible prognosis, which is partly due to difficulties in diagnosing the disease in an early stage. Additional blood-born biomarkers for pancreatic adenocarcinoma are needed. Epigenetic modifications, as changes in DNA methylation, is a fundamental part of carcinogenesis. The aim of this paper is to do an update on cell-free DNA methylation as blood-based biomarkers for pancreatic adenocarcinoma. The current literature including our studies clearly indicates that cell-free DNA methylation has the potential as blood-based diagnostic and prognostic biomarkers for pancreatic adenocarcinoma. However, still no clinical applicable biomarker for pancreatic adenocarcinoma based on DNA methylation do exist. Further well-designed validation studies are needed.

Few prognostic biomarkers are available for pancreatic cancer. The aim of this study is to examine the correlation between the survival of pancreatic adenocarcinoma patients and hypermethylated genes in plasma-derived cell-free DNA.

Consecutive patients with pancreatic adenocarcinoma were prospectively included and staged according to the TNM classification. Methylation-specific PCR of 28 genes was conducted. A survival prediction model independent of cancer stage and stage-specific survival prediction models were developed by multivariable Cox regression analysis using backward stepwise selection.

Ninety-five patients with pancreatic adenocarcinoma were included. Patients with more than 10 hypermethylated genes had a HR of 2.03 (95% CI; 1.15-3.57) compared to patients with fewer hypermethylated genes. Three survival prediction models were developed: Total group; (American Society of Anesthesiologists score (ASA)=3, GSTP1, SFRP2, BNC1, SFRP1, TFPI2, and WNT5A) Risk groups 2, 3 and 4 had a HR of 2.65 (95% CI; 1.24-5.66), 4.34 (95% CI; 1.98-9.51) and 21.19 (95% CI; 8.61-52.15), respectively, compared to risk group 1. Stage I-II; (ASA=3, SFRP2, and MESTv2) Risk groups 2, 3 and 4 had a HR of 4.83 (95% CI; 2.01-11.57), 9.12 (95% CI; 2.18-38.25) and 70.90 (95% CI; 12.63-397.96), respectively, compared to risk group 1. Stage IV; (BMP3, NPTX2, SFRP1, and MGMT) Risk group 2 had a HR of 5.23 (95% CI; 2.13-12.82) compared to risk group 1.

Prediction models based on cell-free DNA hypermethylation stratified pancreatic adenocarcinoma patients into risk groups according to survival. The models have the potential to work as prognostic biomarkers. However, further validation of the results is required to substantiate the findings.

• biomarker
• epigenetics
• methylation
• pancreatic cancer
• prognosis

• biomarker
• epigenetics
• hypermethylation
• pancreatic cancer
• prognosis

• Cell-free DNA
• Diagnostic biomarker
• Epigenetic
• Methylation
• Pancreatic adenocarcinoma
• Pancreatic cancer
• Pancreatitis

Pancreatic ductal adenocarcinoma (PDAC) is often viewed to arise primarily by genetic alterations. However, today we know that many aspects of the cancer phenotype require a crosstalk among these genetic alterations with epigenetic changes. Indeed, aberrant gene expression patterns, driven by epigenetics are fixed by altered signaling from mutated oncogenes and tumor suppressors to define the PDAC phenotype. This conceptual framework may have significant mechanistic value and could offer novel possibilities for treating patients affected with PDAC. In fact, extensive investigations are leading to the development of small molecule drugs that reversibly modify the epigenome. These new ‘epigenetic therapeutics’ discussed herein are promising to fuel a new era of studies, by providing the medical community with new tools to treat this dismal disease.

• DNA methylation
• DNMTs
• HATs
• HDACs
• HMTs
• chromatin
• epigenetics
• noncoding RNAs
• pancreatic cancer
• therapeutics

Nupr1 is a chromatin protein, which cooperates with Kras^G12D to induce PanIN formation and pancreatic cancer development in mice, though the molecular mechanisms underlying this effect remain to be fully characterized. In the current study, we report that Nupr1 acts as a gene modifier of the effect of Kras^G12D-induced senescence by regulating Dnmt1 expression and consequently genome-wide levels of DNA methylation. Congruently, 5-aza-2′-deoxycytydine, a general inhibitor of DNA methylation, reverses the Kras^G12D-induced PanIN development by promoting senescence. This requirement of Nupr1 expression, however, is not restricted to the pancreas since in lung of Nupr1^–/– mice the expression of Kras^G12D induces senescence instead of transformation. Therefore, mechanistically this data reveals that epigenetic events, at least at the level of DNA methylation, modulate the functional outcome of common genetic mutations, such as Kras^G12D, during carcinogenesis. The biomedical relevance of these findings lies in that they support the rational for developing similar therapeutic interventions in human aimed at controlling either the initiation or progression of cancer.

Death Receptor 5 (DR5) agonists demonstrate anti-tumor activity in preclinical models but have yet to demonstrate robust clinical responses. A key limitation may be the lack of patient selection strategies to identify those most likely to respond to treatment. To overcome this limitation, we screened a DR5 agonist Nanobody across >600 cell lines representing 21 tumor lineages and assessed molecular features associated with response. High expression of DR5 and Casp8 were significantly associated with sensitivity, but their expression thresholds were difficult to translate due to low dynamic ranges. To address the translational challenge of establishing thresholds of gene expression, we developed a classifier based on ratios of genes that predicted response across lineages. The ratio classifier outperformed the DR5+Casp8 classifier, as well as standard approaches for feature selection and classification using genes, instead of ratios. This classifier was independently validated using 11 primary patient-derived pancreatic xenograft models showing perfect predictions as well as a striking linearity between prediction probability and anti-tumor response. A network analysis of the genes in the ratio classifier captured important biological relationships mediating drug response, specifically identifying key positive and negative regulators of DR5 mediated apoptosis, including DR5, CASP8, BID, cFLIP, XIAP and PEA15. Importantly, the ratio classifier shows translatability across gene expression platforms (from Affymetrix microarrays to RNA-seq) and across model systems (in vitro to in vivo). Our approach of using gene expression ratios presents a robust and novel method for constructing translatable biomarkers of compound response, which can also probe the underlying biology of treatment response.

• Animals
• Apoptosis/genetics
• Caspase 8/genetics
• Cell Line, Tumor
• Cell Lineage/genetics
• Gene Expression/genetics
• Gene Expression Regulation, Neoplastic/genetics
• Humans
• Mice
• Pancreatic Neoplasms/genetics
• Protein Biosynthesis/genetics
• Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics
• Xenograft Model Antitumor Assays/methods

An improvement in pancreatic cancer treatment represents an urgent medical goal. Late diagnosis and high intrinsic resistance to conventional chemotherapy has led to a dismal overall prognosis that has remained unchanged during the past decades. Increasing knowledge about the molecular pathogenesis of the disease has shown that genetic alterations, such as mutations of K-ras, and especially epigenetic dysregulation of tumor-associated genes, such as silencing of the tumor suppressor p16^ink4a, are hallmarks of pancreatic cancer. Here, we describe genes that are commonly affected by epigenetic dysregulation in pancreatic cancer via DNA methylation, histone acetylation or miRNA (microRNA) expression, and review the implications on pancreatic cancer biology such as epithelial-mesenchymal transition, morphological pattern formation, or cancer stem cell regulation during carcinogenesis from PanIN (pancreatic intraepithelial lesions) to invasive cancer and resistance development. Epigenetic drugs, such as DNA methyltransferases or histone deactylase inhibitors, have shown promising preclinical results in pancreatic cancer and are currently in early phases of clinical development. Combinations of epigenetic drugs with established cytotoxic drugs or targeted therapies are promising approaches to improve the poor response and survival rate of pancreatic cancer patients.

• Pancreatic cancer
• Epigenetics
• DNA methylation
• Histone modification
• microRNA
• Targeted therapy
• Epithelial-mesenchymal transition

• Animals
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/genetics
• Drug Design
• Epigenesis, Genetic/drug effects
• Gene Expression Regulation, Neoplastic
• Genetic Predisposition to Disease
• Humans
• Molecular Targeted Therapy
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/physiopathology
• Phenotype
• Treatment Outcome

• DNA Methylation
• Epigenesis, Genetic
• Histones/metabolism
• Humans
• MicroRNAs/genetics
• Models, Genetic
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/therapy

• CA16359 NCI NIH HHS
• UL1 RR024139 NCRR NIH HHS

• Aneuploidy
• Animals
• Cell Line, Transformed
• Cell Transformation, Neoplastic/genetics
• Chromosomal Instability/genetics
• Epithelial Cells/metabolism
• Epithelial Cells/pathology
• Female
• Genes, myc
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Phenotype
• Proto-Oncogene Proteins c-mdm2/genetics

• Y99 CA999999 NCI NIH HHS
• Z99 CA999999 Intramural NIH HHS