A5039511927- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- RNA modifications and cancer
- Immunotherapy and Immune Responses
- Ovarian cancer diagnosis and treatment
- Acute Myeloid Leukemia Research
- Prostate Cancer Treatment and Research
- FOXO transcription factor regulation
- Cancer-related molecular mechanisms research
- Folate and B Vitamins Research
- Immune Cell Function and Interaction
- vaccines and immunoinformatics approaches
- Genomics and Chromatin Dynamics
- RNA Interference and Gene Delivery
- Phytoestrogen effects and research
- Tea Polyphenols and Effects
- Estrogen and related hormone effects
- Cancer Cells and Metastasis
- Immunodeficiency and Autoimmune Disorders
- Genetic Syndromes and Imprinting
- DNA Repair Mechanisms
- MicroRNA in disease regulation
- TGF-β signaling in diseases
- RNA Research and Splicing
- Vitamin D Research Studies
University of Nebraska Medical Center
2016-2025
Nebraska Medical Center
2013-2024
Roswell Park Comprehensive Cancer Center
2008-2023
Therapeutics Clinical Research
2023
Advanced Cancer Therapeutics
2023
Susan Thompson Buffett Foundation
2015-2016
Fred and Pamela Buffett Cancer Center
2015-2016
University of Nebraska at Omaha
2013-2015
The Eppley Laboratory (United States)
2015
Icahn School of Medicine at Mount Sinai
2014
Chromatin methylation is necessary for stable repression of gene expression during mammalian development. During cell division, DNMT1 maintains the DNA pattern newly synthesized daughter strand, while G9a methylates H3K9. Here, shown to directly bind both in vivo and vitro colocalize nucleus replication. The complex colocalizes with dimethylated H3K9 (H3K9me2) at replication foci. Similarly, another histone methyltransferase, SUV39H1, on heterochromatic regions nucleoli exclusively before...
A hallmark of human cancer is global DNA hypomethylation (GDHO), but the mechanisms accounting for this defect and its pathological consequences have not been investigated in epithelial ovarian (EOC). In EOC, GDHO was associated with advanced disease reduced overall disease-free survival. (+) EOC tumors displayed a proliferative gene expression signature, including FOXM1 CCNE1 overexpression. Furthermore, these enriched within genomic blocks (hypomethylated blocks) that overlapped...
FOXM1 is frequently overexpressed in cancer, but this has not been studied a comprehensive manner. We utilized genotype-tissue expression (GTEx) normal and The Cancer Genome Atlas (TCGA) tumor data to define expression, including its isoforms, determine the genetic alterations that promote cancer. Additionally, we used human fallopian tube epithelial (FTE) cells dissect role of Retinoblastoma (Rb)-E2F Cyclin E1 regulation, novel embryonic kidney cell (HEK293T) CRISPR knockout model...
DNA methyltransferase 1 (DNMT1)-deficient mice are tumor-prone, and this has been proposed to result from the induction of genomic instability. To address whether loss DNMT1, or related protein DNMT3b, results in instability human cancer cells, we used a near-diploid colorectal cell line, HCT116, which one both DNMT genes were disrupted by homologous recombination. Array-based comparative hybridization analyses indicated that double, but not single, knock-out cells display two specific...
Herein we report a novel method for determining genomic DNA methylation that utilizes liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) to measure 5-methyl-2'-deoxycytidine levels following enzymatic hydrolysis of DNA. LC separation from the four deoxyribonucleosides, ribonucleosides, and 5-methyl-2'-cytidine, RNA product, has been achieved within 15 min. In combination with ESI-MS/MS detection, reported is highly specific extremely sensitive limit...
Inhibitors of DNA methyltransferase, typified by 5-aza-2′-deoxycytidine (5-Aza-CdR), induce the expression genes transcriptionally down-regulated de novo methylation in tumor cells. We utilized gene microarrays to examine effects 5-Aza-CdR treatment HT29 colon adenocarcinoma This analysis revealed induction a set that implicated IFN signaling cellular response 5-Aza-CdR. Subsequent investigations this correlates with signal transducer and activator transcription (STAT) 1, 2, 3 their...
Three Aedes albopictus (mosquito) cell lines persistently infected with Sindbis virus excluded the replication of both homologous (various strains Sindbis) and heterologous (Aura, Semliki Forest, Ross River) alphaviruses. In contrast, an unrelated flavivirus, yellow fever virus, replicated equally well in uninfected cells each line. Forest are among most distantly related alphaviruses, our results thus indicate that mosquito broadly able to exclude other alphaviruses but exclusion is...
The roles of DNA methyltransferase-2 (DNMT2) enzymes are controversial; whether DNMT2 functions primarily as a nuclear methyltransferase or cytoplasmic tRNA methyltransferase, and activity impacts development, dnmt2 mutant mice Drosophila lack phenotypes. Here we show that morpholino knockdown Dnmt2 protein in zebrafish embryos confers differentiation defects particular organs, including the retina, liver, brain. Importantly, proper organ required cytoplasm, not nucleus. Furthermore,...
Abstract The cancer–testis/cancer germline antigen, NY-ESO-1, is a vaccine target in epithelial ovarian cancer (EOC), but its limited expression barrier to efficacy. As NY-ESO-1 regulated by DNA methylation, we hypothesized that methyltransferase inhibitors may augment therapy. In agreement, global hypomethylation EOC was associated with the presence of circulating antibodies NY-ESO-1. Preclinical studies using cell lines showed decitabine treatment enhanced both and NY-ESO-1–specific...
Background : Global DNA hypomethylation may result in chromosomal instability and oncogene activation, as a surrogate of systemic methylation activity, be associated with breast cancer risk. Methods Samples data were obtained from women incident early-stage (I–IIIa) who free, frequency matched on age race. In preliminary analyses, genomic leukocyte was determined by measuring 5-methyldeoxycytosine (5-mdC), well analysis the LINE-1-repetitive element. Further analyses used only 5-mdC levels....
// Wa Zhang 1, 10 , Carter J. Barger 1 Kevin H. Eng 4 David Klinkebiel 2 Petra A. Link 3 Angela Omilian 5 Wiam Bshara Kunle Odunsi 6, 7, 8 Adam R. Karpf 9 Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA Department Biochemistry and Molecular Biology, Pharmacology, Roswell Park Institute, Buffalo, NY, Biostatistics Bioinformatics, Pathology, 6 Gynecologic Oncology, 7 Immunology, Center Immunotherapy, Fred Pamela Buffett Current address: Wilmer Eye...
Cancer stem cells (CSC) play a central role in cancer metastasis and development of drug resistance. miRNA are important regulating CSC properties considered potential therapeutic targets. Here we report that miR-328-3p (miR-328) is significantly upregulated ovarian CSC. High expression miR-328 maintained by directly targeting DNA damage binding protein 2, which has been shown previously to inhibit Reduced activity ERK signaling CSC, mainly due low level reactive oxygen species, contributed...
CCNE1-amplified ovarian cancers (OVCAs) and endometrial (EMCAs) are associated with platinum resistance poor survival, representing a clinically unmet need. We hypothesized that dysregulated cell-cycle progression promoted by CCNE1 overexpression would lead to increased sensitivity low-dose WEE1 inhibition ataxia telangiectasia Rad3-related (ATR) (WEE1i-ATRi), thereby optimizing efficacy tolerability. The addition of ATRi WEE1i is required block feedback activation ATR signaling mediated...
Transcriptional silencing of tumor suppressor genes by DNA methylation occurs in cancer cell lines and human tumors. This has led to the pursuit methyltransferase inhibition as a drug target. 5-Aza-2′-deoxycytidine [5-aza-CdR (decitabine)], potent inhibitor methyltransferase, is currently clinical trials for treatment solid tumors leukemia. The efficacy 5-aza-CdR may be related induction methylation-silenced genes, genomic hypomethylation, and/or enzyme-DNA adduct formation. Here, we test...
DNA methylation and histone are two key epigenetic modifications that help govern heterochromatin dynamics. The roles for these chromatin-modifying activities in directing tissue-specific development remain largely unknown. To address this issue, we examined the of methyltransferase 1 (Dnmt1) H3K9 Suv39h1 zebra fish development. Knockdown Dnmt1 embryos caused defects terminal differentiation intestine, exocrine pancreas, retina. Interestingly, not all tissues required Dnmt1, as liver...
It remains unclear to what extent drugs targeting transcriptional repressor complexes affect global gene expression in cells derived from target and nontarget human tissues. To address this question, we used genome-wide analysis using microarrays analyze the response of three tumor one normal epithelial cell line treatment with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-CdR). Notably, found that 5-aza-CdR induced a limited number genes (mean, 0.67%; range, 0.17-1.8% 25,940...
Purpose The nucleoside analog 5-aza-2′-deoxycytidine (5-aza-CdR, decitabine) is a potent inhibitor of DNA methylation in vitro. Cellular treatment with this agent induces the re-expression methylation-silenced genes. It remains unclear to what extent compound inhibits vivo. A clinical study was designed examine molecular effects and toxicity continuous 1-week intravenous infusion decitabine solid tumor patients. Methods Ten patients refractory tumors were included study. Decitabine...
Although DNA methylation is critical for proper embryonic and tissue-specific development, how different methyltransferases affect development their targets remains unknown. We address this issue in zebrafish through antisense-based morpholino knockdown of Dnmt3 Dnmt1. Our data reveal that required neurogenesis, its absence results profound defects brain retina. Interestingly, other organs such as intestine remain unaffected suggesting requirements Dnmt3. Further, comparison Dnmt1 phenotypes...