A5039169226- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- RNA modifications and cancer
- Chronic Lymphocytic Leukemia Research
- Protein Degradation and Inhibitors
- Lung Cancer Treatments and Mutations
- Acute Myeloid Leukemia Research
- Cancer Genomics and Diagnostics
- Histone Deacetylase Inhibitors Research
- Multiple Myeloma Research and Treatments
- Ubiquitin and proteasome pathways
- Prostate Cancer Treatment and Research
- Nonmelanoma Skin Cancer Studies
- Cancer-related Molecular Pathways
- Immune Cell Function and Interaction
- Genomics and Chromatin Dynamics
- Immunotherapy and Immune Responses
- Neuroblastoma Research and Treatments
- RNA Research and Splicing
- Genomics, phytochemicals, and oxidative stress
- Model Reduction and Neural Networks
- MicroRNA in disease regulation
- Sarcoma Diagnosis and Treatment
- Biochemical and Molecular Research
- Parallel Computing and Optimization Techniques
GlaxoSmithKline (United States)
2015-2024
University of Colorado Boulder
2024
Flatiron Institute
2023-2024
Target (United States)
2024
Flatiron Health (United States)
2023-2024
University of Rochester
2023
Lawrence Berkeley National Laboratory
2023
GlaxoSmithKline (India)
2022
United States Agency for International Development
2022
Kalamazoo College
2022
Loss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function polycomb repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing the MHC-I processing pathway (MHC-I APP), promoting evasion T cell-mediated immunity. APP gene promoters low cancers harbor bivalent activating H3K4me3 and H3K27me3 histone modifications, basal expression restricting...
Trimethylation of histone H3 on lysine 27 (H3K27me3) is a repressive posttranslational modification mediated by the methyltransferase EZH2. EZH2 component polycomb complex 2 and overexpressed in many cancers. In B-cell lymphomas, its substrate preference frequently altered through somatic mutation Y641 residue. Herein, we identify A677 to glycine (A677G) among lymphoma cell lines primary tumor specimens. Similar mutant lines, an A677G line revealed aberrantly elevated H3K27me3 decreased...
The histone H3-lysine 27 (H3K27) methyltransferase EZH2 plays a critical role in regulating gene expression, and its aberrant activity is linked to the onset progression of cancer. As part drug discovery program targeting EZH2, we have identified highly potent, selective, SAM-competitive, cell-active inhibitors, including GSK926 (3) GSK343 (6). These compounds are small molecule chemical tools that would be useful further explore biology EZH2.
Increased activity of the epigenetic modifier EZH2 has been associated with different cancers. However, evidence for a functional role in tumorigenesis vivo remains poor, particular metastasizing solid Here we reveal central roles promoting growth and metastasis cutaneous melanoma. In melanoma mouse model, conditional Ezh2 ablation as much treatment preclinical inhibitor GSK503 stabilizes disease through inhibition virtually abolishes metastases formation without affecting normal melanocyte...
Bladder cancer with loss of KDM6A expression is vulnerable to inhibition EZH2.
DNA methylation plays a critical role during development, particularly in repressing retrotransposons. The mammalian landscape is dependent on the combined activities of canonical maintenance enzyme Dnmt1 and de novo Dnmts, 3a 3b. Here, we demonstrate that displays activity vitro vivo with specific retrotransposon targeting. We used whole-genome bisulfite long-read Nanopore sequencing genetically engineered methylation-depleted mouse embryonic stem cells to provide an in-depth assessment...
DNA methylation plays a crucial role in the regulation of gene expression and chromatin organization within normal eukaryotic cells. In cancer, however, global patterns are altered with hypomethylation repeat-rich intergenic regions hypermethylation subset CpG-dense gene-associated (CpG islands). Extensive research has revealed cellular machinery that catalyzes methylation, as well several large protein complexes mediate transcriptional repression hypermethylated genes. However, is only just...
BET family proteins are epigenetic regulators known to control expression of genes involved in cell growth and oncogenesis. Selective inhibitors exhibit potent anti-proliferative activity a number hematologic cancer models, part through suppression the MYC oncogene downstream Myc-driven pathways. However, little is currently about solid tumor whether down-regulation contributes sensitivity. Here we provide evidence for inhibitor neuroblastoma, pediatric associated with high frequency MYCN...
Abstract Tumor suppressor gene silencing by DNA hypermethylation contributes to tumorigenesis in many tumor types. This aberrant methylation may be due increased expression and activity of methyltransferases, which catalyze the transfer methyl groups from S-adenosylmethionine cytosines CpG dinucleotides. Elevated maintenance methyltransferase, methyltransferase 1 (DNMT-1), has been shown carcinomas colon, lung, liver, prostate. Based on nearly ubiquitous alterations both retinoblastoma...
Evasion of the potent tumour suppressor activity p53 is one hurdles that must be overcome for cancer cells to escape normal regulation cellular proliferation and survival. In addition frequent loss function mutations, wild-type can also suppressed post-translationally through several mechanisms, including PRMT5. Here we describe broad anti-proliferative potent, selective, reversible inhibitors protein arginine methyltransferase 5 (PRMT5) GSK3326595 in human cell lines representing both...
Enhancer of zeste homolog 2 (EZH2) activity is dysregulated in many cancers.This phase I study determined the safety, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics intravenously administered, highly selective EZH2 inhibitor, GSK2816126, (NCT02082977). Doses GSK2816126 ranged from 50 to 3,000 mg twice weekly, was given 3-weeks-on/1-week-off 28-day cycles. Eligible patients had solid tumors or B-cell lymphomas with no available standard treatment regimen.Forty-one (21...
CARM1 is an arginine methyltransferase with diverse histone and non-histone substrates implicated in the regulation of cellular processes including transcriptional co-activation RNA processing. overexpression has been reported multiple cancer types shown to modulate oncogenic pathways vitro studies. Detailed understanding mechanism action oncogenesis limited by a lack selective tool compounds, particularly for vivo We describe identification characterization of, our knowledge, first potent...
Abstract Transcriptional silencing of tumor suppressor genes by DNA methylation plays an important role in tumorigenesis. These aberrant epigenetic modifications may be mediated part elevated methyltransferase levels. 1 (DNMT1), particular, is overexpressed many types. Recently, we showed that Dnmt1 transcriptionally regulated E2F transcription factors and retinoblastoma protein (pRb) inactivation induces Dnmt1. Based on these observations, investigated regulation polyomavirus oncogenes,...
Lysine specific demethylase 1 (LSD1) is a histone modifying enzyme that suppresses gene expression through demethylation of lysine 4 on H3. The anti-tumor activity GSK2879552 and GSK-LSD1, potent, selective irreversible inactivators LSD1, has previously been described. Inhibition LSD1 results in cytostatic growth inhibitory effect range acute myeloid leukemia cell lines. To enhance the therapeutic potential inhibition this disease setting, combination all-trans retinoic acid was explored....