Targeting Myc signaling pathway by inhibition of histone demethylase JMJD2B
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE45970 | GEO | 2014/01/01
SECONDARY ACCESSION(S): PRJNA196763
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-01-01 | E-GEOD-45970 | biostudies-arrayexpress
Project description:Epigenetic alterations appear to modulate Myc signaling. We investigated the role of the histone demethylase JMJD2B in Myc-mediated neuroblastoma pathogenesis. We demonstrate that Myc physically interacts with and recruits this epigenetic modifier, which removes repressive H3K9 methyl marks from Myc-target genes. JMJD2B regulates neuroblastoma proliferation and, together with MYCN amplification, identifies a subgroup of poor prognosis patients. We identify a novel histone demethylase inhibitor, ciclopirox, which targets JMJD2B and, consequently, Myc signaling, thereby inhibiting neuroblastoma proliferation and inducing differentiation. In xenograft studies, genetic and pharmacologic inhibition of JMJD2B resulted in significant tumor growth restriction. Our findings provide insight into epigenetic regulation of Myc via histone methylation and proof-of-concept for pharmacologic inhibition of histone demethylases to target Myc signaling in cancer. 8 samples were transfected with two different siRNAs for control, JMJD2B, MYCN and JARID1A.
2014-01-01 | E-GEOD-45967 | biostudies-arrayexpress
Project description:Epigenetic alterations appear to modulate Myc signaling. We investigated the role of the histone demethylase JMJD2B in Myc-mediated neuroblastoma pathogenesis. We demonstrate that Myc physically interacts with and recruits this epigenetic modifier, which removes repressive H3K9 methyl marks from Myc-target genes. JMJD2B regulates neuroblastoma proliferation and, together with MYCN amplification, identifies a subgroup of poor prognosis patients. We identify a novel histone demethylase inhibitor, ciclopirox, which targets JMJD2B and, consequently, Myc signaling, thereby inhibiting neuroblastoma proliferation and inducing differentiation. In xenograft studies, genetic and pharmacologic inhibition of JMJD2B resulted in significant tumor growth restriction. Our findings provide insight into epigenetic regulation of Myc via histone methylation and proof-of-concept for pharmacologic inhibition of histone demethylases to target Myc signaling in cancer. 8 samples were treated with vehicle or ciclopirox.
2014-01-01 | E-GEOD-45969 | biostudies-arrayexpress
Project description:Epigenetic alterations appear to modulate Myc signaling. We investigated the role of the histone demethylase JMJD2B in Myc-mediated neuroblastoma pathogenesis. We demonstrate that Myc physically interacts with and recruits this epigenetic modifier, which removes repressive H3K9 methyl marks from Myc-target genes. JMJD2B regulates neuroblastoma proliferation and, together with MYCN amplification, identifies a subgroup of poor prognosis patients. We identify a novel histone demethylase inhibitor, ciclopirox, which targets JMJD2B and, consequently, Myc signaling, thereby inhibiting neuroblastoma proliferation and inducing differentiation. In xenograft studies, genetic and pharmacologic inhibition of JMJD2B resulted in significant tumor growth restriction. Our findings provide insight into epigenetic regulation of Myc via histone methylation and proof-of-concept for pharmacologic inhibition of histone demethylases to target Myc signaling in cancer.
2014-01-01 | GSE45969 | GEO
Project description:Epigenetic alterations appear to modulate Myc signaling. We investigated the role of the histone demethylase JMJD2B in Myc-mediated neuroblastoma pathogenesis. We demonstrate that Myc physically interacts with and recruits this epigenetic modifier, which removes repressive H3K9 methyl marks from Myc-target genes. JMJD2B regulates neuroblastoma proliferation and, together with MYCN amplification, identifies a subgroup of poor prognosis patients. We identify a novel histone demethylase inhibitor, ciclopirox, which targets JMJD2B and, consequently, Myc signaling, thereby inhibiting neuroblastoma proliferation and inducing differentiation. In xenograft studies, genetic and pharmacologic inhibition of JMJD2B resulted in significant tumor growth restriction. Our findings provide insight into epigenetic regulation of Myc via histone methylation and proof-of-concept for pharmacologic inhibition of histone demethylases to target Myc signaling in cancer.
2014-01-01 | GSE45967 | GEO
Project description:Targeting Myc signaling pathway by inhibition of histone demethylase JMJD2B
| PRJNA196763 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-01-08 | GSE143151 | GEO
Project description:Endothelial cells play an important role in maintenance of the vascular system and the repair after injury. Under proinflammatory conditions, endothelial cells can acquire a mesenchymal phenotype by a process named endothelial-to-mesenchymal transition (EndMT), which affects the functional properties of endothelial cells. Here, we investigated the epigenetic control of EndMT. We show that the histone demethylase JMJD2B is induced by EndMT-promoting, proinflammatory, and hypoxic conditions. Silencing of JMJD2B reduced TGF-?2-induced expression of mesenchymal genes, prevented the alterations in endothelial morphology and impaired endothelial barrier function. Endothelial-specific deletion of JMJD2B in vivo confirmed a reduction of EndMT after myocardial infarction. EndMT did not affect global H3K9me3 levels but induced a site-specific reduction of repressive H3K9me3 marks at promoters of mesenchymal genes, such as Calponin (CNN1), and genes involved in TGF-? signaling, such as AKT Serine/Threonine Kinase 3 (AKT3) and Sulfatase 1 (SULF1). Silencing of JMJD2B prevented the EndMT-induced reduction of H3K9me3 marks at these promotors and further repressed these EndMT-related genes. Our study reveals that endothelial identity and function is critically controlled by the histone demethylase JMJD2B, which is induced by EndMT-promoting, proinflammatory, and hypoxic conditions, and supports the acquirement of a mesenchymal phenotype.
| S-EPMC7049147 | biostudies-literature
Project description:Ligand-activated liver X receptor α (LXRα) upregulates the expression of hepatic lipogenic genes, which leads to triglyceride (TG) accumulation, resulting in nonalcoholic fatty liver disease (NAFLD). Thus, LXRα regulation may provide a novel therapeutic target against NAFLD. However, histone methylation-mediated epigenetic regulation involved in LXRα-dependent lipogenesis is poorly understood. In this study, we investigated the functional role of the histone demethylase Jumonji domain-containing protein 2B (JMJD2B) in LXRα-dependent lipogenesis. JMJD2B expression level was upregulated in HepG2 cells treated with LXRα agonist T0901317 or palmitate and the liver of mice administered with T0901317 or fed a high-fat diet. Knockdown of JMJD2B using siRNA abrogated T0901317-induced LXRα-dependent lipogenic gene expression and lowered intracellular TG accumulation. Conversely, overexpression of JMJD2B in HepG2 cells upregulated the expression of LXRα-dependent lipogenic genes, in line with increased intracellular TG levels. JMJD2B overexpression or T0901317 treatment induced the recruitment of JMJD2B and LXRα to LXR response elements (LXRE) in the promoter region of LXRα-target gene and reduced the enrichment of H3K9me2 and H3K9me3 in the vicinity of the LXRE. Furthermore, JMJD2B enhanced T0901317 or LXRα-induced transcriptional activities of reporters containing LXRE. A co-immunoprecipitation assay revealed that JMJD2B interacted with activated LXRα. Moreover, overexpression of JMJD2B in mice resulted in upregulation of hepatic LXRα-dependent lipogenic genes, consistent with development of hepatic steatosis. Taken together, these results indicate that JMJD2B plays a role in LXRα-mediated lipogenesis via removing the repressive histone marks, H3K9me2 and H3K9me3, at LXRE, which might contribute to hepatic steatosis.
| S-EPMC7664202 | biostudies-literature
Project description:Understanding the epigenetic mechanisms underlying the progression of hepatic steatosis is important for identifying new therapeutic targets against nonalcoholic fatty liver disease (NAFLD). We investigated the functional role of histone demethylase JMJD2B in the pathologic regulation of hepatic steatosis. JMJD2B expression was markedly increased in HepG2 cells treated with palmitate and oleate or liver X receptor agonist T09013178 and in the liver of high-fat diet (HFD)-induced obese mice. Overexpression of JMJD2B using adenovirus in HepG2 cells stimulated the expression of peroxisome proliferator-activated receptor ?2 (PPAR?2) and its steatosis target genes associated with fatty acid uptake and lipid droplet formation, resulting in increased intracellular triglyceride (TG) accumulation. Conversely, knocking down JMJD2B using siRNA reversed JMJD2B-mediated effects in HepG2 cells. The JMJD2B-dependent upregulation of PPAR?2 was associated with the removal of di- and trimethylation of histone H3 lysine 9 on the promoter of PPAR?2. Furthermore, exogeneous expression of JMJD2B using adenovirus in mice resulted in hepatic steatosis when fed a HFD, which was accompanied with increased expression of hepatic PPAR?2 and its steatosis target genes. Together, our results provide novel insights into the pivotal role of JMJD2B in the development of hepatic steatosis through upregulation of PPAR?2 and steatosis target genes.
| S-EPMC6137221 | biostudies-literature