| Records |
| Author |
Fogel, O.; Richard-Miceli, C.; Tost, J. |
| Title |
Epigenetic Changes in Chronic Inflammatory Diseases |
Type |
Journal Article |
| Year |
2017 |
Publication |
Advances in Protein Chemistry and Structural Biology |
Abbreviated Journal |
Adv Protein Chem Struct Biol |
| Volume |
106 |
Issue |
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Pages |
139-189 |
| Keywords |
Behcet's disease; Crohn's disease; DNA methylation; Ewas; Epigenetics; Histone modifications; Inflammatory bowel disease; Psoriasis; Spondyloarthritis; Ulcerative colitis |
| Abstract |
The number of people diagnosed with chronic inflammatory diseases has increased noteworthy in the last 40 years. Spondyloarthritis (SpA), inflammatory bowel diseases (IBD), and psoriasis are the most frequent chronic inflammatory diseases, resulting from a combination of genetic predisposition and environmental factors. Epigenetic modifications include DNA methylation, histone modifications, and small and long noncoding RNAs. They are influenced by environmental exposure, life-style, and aging and have recently been shown to be altered in many complex diseases including inflammatory diseases. While epigenetic modifications have been well characterized in other diseases such as cancer and autoimmune diseases, knowledge on changes in inflammatory diseases is lagging behind with some disease-specific differences. While the DNA methylation profile of different cell types in patients with IBD has been relatively well described, less is known on changes implicated in psoriasis, and no systematic genome-wide studies have so far been performed in SpA. In this chapter, we review in detail the reported changes in patterns of DNA methylation and posttranslational histone modifications in chronic inflammatory diseases highlighting potential connections between disease-associated pathophysiological changes such as the dysbiosis of the microbiome or genetic variations associated with disease susceptibility and the epigenome. We also discuss important parameters of meaningful epigenetic studies such as the use of well defined, disease-relevant cell populations, and elude on the potential future of engineering of the epigenome in inflammatory diseases. |
| Address |
Laboratory for Epigenetics and Environment, Centre National de Genotypage, CEA-Institut de Genomique, Evry, France. Electronic address: tost@cng.fr |
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English |
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| ISSN |
1876-1623 |
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| Notes |
PMID:28057210 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial  |
96374 |
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| Author |
Tahara, T.; Hirata, I.; Nakano, N.; Nagasaka, M.; Nakagawa, Y.; Shibata, T.; Ohmiya, N. |
| Title |
Comprehensive DNA Methylation Profiling of Inflammatory Mucosa in Ulcerative Colitis |
Type |
Journal Article |
| Year |
2017 |
Publication |
Inflammatory Bowel Diseases |
Abbreviated Journal |
Inflamm Bowel Dis |
| Volume |
23 |
Issue |
1 |
Pages |
165-173 |
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| Abstract |
INTRODUCTION: Aberrant DNA methylation frequently occurs in the inflammatory mucosa in ulcerative colitis (UC) and is involved in UC-related tumorigenesis. We performed comprehensive DNA methylation profiling of the promoter regions of the inflamed rectal mucosae of patients with UC. DESIGN: The methylation status of the promoter CpG islands (CGIs) of 45 cancer/inflammation or age-related candidate genes and the LINE1 repetitive element were examined in the colonic mucosae of 84 cancer-free patients with UC by bisulfite pyrosequencing. Methylation status of selected genes (DPYS, N33, MIR1247, GSTP1, and SOX11) was also determined in 14 neoplastic lesions (5 with high-grade dysplasia and 9 with carcinoma) and 8 adjacent tissues derived from 12 patients. An Infinium HumanMethylation450 BeadChip array was used to characterize the methylation status of >450,000 CpG sites for 10 patients with UC. RESULTS: Clustering analysis based on the methylation status of the candidate genes clearly distinguished the inflammatory samples from the noninflammatory samples. The hypermethylation of the promoter CGIs strongly correlated with increased disease duration, which is a known risk factor for the development of colon cancer. Genome-wide methylation analyses revealed a high rate of hypermethylation in the severe phenotype of UC, particularly at the CGIs. Exclusively hypermethylated promoter CGIs in the severe phenotypes were significantly related to genes involved in biosynthetic processes, the regulation of metabolic processes, and nitrogen compound metabolic processes. CONCLUSION: Our findings suggest the potential utility of DNA methylation as a molecular marker and therapeutic target for UC-related tumorigenesis. |
| Address |
*Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan; and daggerDepartment of Gastroenterology, Tanimukai Hospital Japan, Nishinomiya, Japan |
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English |
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1078-0998 |
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| Notes |
PMID:27930411 |
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no |
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ref @ user @ |
Serial |
96375 |
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Li, M.; Xiao, A.; Floyd, D.; Olmez, I.; Lee, J.; Godlewski, J.; Bronisz, A.; Bhat, K.P.L.; Sulman, E.P.; Nakano, I.; Purow, B. |
| Title |
CDK4/6 inhibition is more active against the glioblastoma proneural subtype |
Type |
Journal Article |
| Year |
2017 |
Publication |
Oncotarget |
Abbreviated Journal |
Oncotarget |
| Volume |
8 |
Issue |
33 |
Pages |
55319-55331 |
| Keywords |
Cdk4/6; glioblastoma; mesenchymal; palbociclib; proneural |
| Abstract |
Glioblastoma (GBM) is the most common and lethal brain tumor. Gene expression profiling has classified GBM into distinct subtypes, including proneural, mesenchymal, and classical, and identifying therapeutic vulnerabilities of these subtypes is an extremely high priority. We leveraged The Cancer Genome Atlas (TCGA) data, in particular for microRNA expression, to seek druggable core pathways in GBM. The E2F1-regulated miR-17 92 cluster and its analogs are shown to be highly expressed in proneural GBM and in GSC lines, suggesting the E2F cell cycle pathway might be a key driver in proneural GBM. Consistently, CDK4/6 inhibition with palbociclib preferentially inhibited cell proliferation in vitro in a majority of proneural GSCs versus those of other subtypes. Palbociclib treatment significantly prolonged survival of mice with established intracranial xenografts of a proneural GSC line. We show that most of these sensitive PN GSCs expressed higher levels of CDK6 and had intact Rb1, while two GSC lines with CDK4 overexpression and null Rb1 were highly resistant to palbociclib. Importantly, palbociclib treatment of proneural GSCs upregulated mesenchymal-associated markers and downregulated proneural-associated markers, suggesting that CDK4/6 inhibition induced proneural-mesenchymal transition and underscoring the enhanced role of the E2F cell cycle pathway in the proneural subtype. Lastly, the combination of palbociclib and N,N-diethylaminobenzaldehyde, an inhibitor of the mesenchymal driver ALDH1A3, showed strong synergistic inhibitory effects against proneural GSC proliferation. Taken together, our results reveal that proneural GBM has increased vulnerability to CDK4/6 inhibition, and the proneural subtype undergoes dynamic reprogramming upon palbociclib treatment-suggesting the need for a combination therapeutic strategy. |
| Address |
Neuro-Oncology Division, Department of Neurology, University of Virginia, Charlottesville, VA, USA |
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English |
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1949-2553 |
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| Notes |
PMID:28903422 |
Approved |
no |
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ref @ user @ |
Serial |
96569 |
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| Author |
Heffernan, J.M.; McNamara, J.B.; Borwege, S.; Vernon, B.L.; Sanai, N.; Mehta, S.; Sirianni, R.W. |
| Title |
PNIPAAm-co-Jeffamine(R) (PNJ) scaffolds as in vitro models for niche enrichment of glioblastoma stem-like cells |
Type |
Journal Article |
| Year |
2017 |
Publication |
Biomaterials |
Abbreviated Journal |
Biomaterials |
| Volume |
143 |
Issue |
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Pages |
149-158 |
| Keywords |
Brain tumor initiating cells; Cancer stem cells; Radioresistance; Temperature responsive polymer scaffolds; Tissue engineering |
| Abstract |
Glioblastoma (GBM) is the most common adult primary brain tumor, and the 5-year survival rate is less than 5%. GBM malignancy is driven in part by a population of GBM stem-like cells (GSCs) that exhibit indefinite self-renewal capacity, multipotent differentiation, expression of neural stem cell markers, and resistance to conventional treatments. GSCs are enriched in specialized niche microenvironments that regulate stem phenotypes and support GSC radioresistance. Therefore, identifying GSC-niche interactions that regulate stem phenotypes may present a unique target for disrupting the maintenance and persistence of this treatment resistant population. In this work, we engineered 3D scaffolds from temperature responsive poly(N-isopropylacrylamide-co-Jeffamine M-1000(R) acrylamide), or PNJ copolymers, as a platform for enriching stem-specific phenotypes in two molecularly distinct human patient-derived GSC cell lines. Notably, we observed that, compared to conventional neurosphere cultures, PNJ cultured GSCs maintained multipotency and exhibited enhanced self-renewal capacity. Concurrent increases in expression of proteins known to regulate self-renewal, invasion, and stem maintenance in GSCs (NESTIN, EGFR, CD44) suggest that PNJ scaffolds effectively enrich the GSC population. We further observed that PNJ cultured GSCs exhibited increased resistance to radiation treatment compared to GSCs cultured in standard neurosphere conditions. GSC radioresistance is supported in vivo by niche microenvironments, and this remains a significant barrier to effectively treating these highly tumorigenic cells. Taken in sum, these data indicate that the microenvironment created by synthetic PNJ scaffolds models niche enrichment of GSCs in patient-derived GBM cell lines, and presents tissue engineering opportunities for studying clinically important behaviors such as radioresistance in vitro. |
| Address |
Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W Thomas Ave, Phoenix, AZ, 85013, USA; School of Biological and Health Systems Engineering, Arizona State University, PO Box 879709, Tempe, AZ, 85287, USA. Electronic address: rachael.sirianni@dignityhealth.org |
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English |
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0142-9612 |
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| Notes |
PMID:28802102 |
Approved |
no |
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ref @ user @ |
Serial |
96570 |
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| Author |
Klumpp, L.; Sezgin, E.C.; Skardelly, M.; Eckert, F.; Huber, S.M. |
| Title |
KCa3.1 channels and glioblastoma: in vitro studies |
Type |
Journal Article |
| Year |
2017 |
Publication |
Current Neuropharmacology |
Abbreviated Journal |
Curr Neuropharmacol |
| Volume |
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Issue |
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Pages |
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| Keywords |
γH2AX foci; Aldh1a3; Gbm; GSCs; IKCa; Kcnn4; Sk4; radioresistance |
| Abstract |
Several tumor entities including brain tumors aberrantly overexpress intermediate conductance Ca2+ activated KCa3.1 K+ channels. These channels contribute significantly to the transformed phenotype of the tumor cells. By modulating membrane potential, cell volume, Ca2+ signals and the respiration chain, KCa3.1 channels in both, plasma and inner mitochondrial membrane, have been demonstrated to regulate many cellular processes such as migration and tissue invasion, metastasis, cell cycle progression, oxygen consumption and metabolism, DNA damage response and cell death of cancer cells. Moreover, KCa3.1 channels have been shown to crucially contribute to resistance against radiotherapy suggesting KCa3.1 channels as promising new targets of future anti-cancer therapies. The present article summarizes our current knowledge of the molecular signaling upstream and downstream and the effector functions of KCa3.1 channel activity in tumor cells in general and in glioblastoma cells in particular. In addition, it presents original in vitro data on KCa3.1 channel expression in subtypes of glioblastoma stem(-like) cells proposing KCa3.1 as marker for the mesenchymal subgroup of cancer stem cells. Moreover, the data suggest that KCa3.1 contributes to the therapy resistance of mesenchymal glioblastoma stem cells. |
| Address |
Department of Radiation Oncology University of Tubingen Hoppe-Seyler-Str. 3 72076 Tubingen. Germany |
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English |
Summary Language |
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Edition |
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| ISSN |
1570-159X |
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| Notes |
PMID:28786347 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
96571 |
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