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https://www.readbyqxmd.com/read/27897169/ezh1-and-ezh2-promote-skeletal-growth-by-repressing-inhibitors-of-chondrocyte-proliferation-and-hypertrophy
#1
Julian C Lui, Presley Garrison, Quang Nguyen, Michal Ad, Chithra Keembiyehetty, Weiping Chen, Youn Hee Jee, Ellie Landman, Ola Nilsson, Kevin M Barnes, Jeffrey Baron
Histone methyltransferases EZH1 and EZH2 catalyse the trimethylation of histone H3 at lysine 27 (H3K27), which serves as an epigenetic signal for chromatin condensation and transcriptional repression. Genome-wide associated studies have implicated EZH2 in the control of height and mutations in EZH2 cause Weaver syndrome, which includes skeletal overgrowth. Here we show that the combined loss of Ezh1 and Ezh2 in chondrocytes severely impairs skeletal growth in mice. Both of the principal processes underlying growth plate chondrogenesis, chondrocyte proliferation and hypertrophy, are compromised...
November 29, 2016: Nature Communications
https://www.readbyqxmd.com/read/27852821/meg3-long-noncoding-rna-contributes-to-the-epigenetic-regulation-of-epithelial-mesenchymal-transition-in-lung-cancer-cell-lines
#2
Minoru Terashima, Shoichiro Tange, Akihiko Ishimura, Takeshi Suzuki
Histone methylation is implicated in a number of biological and pathological processes including cancer development. In this study, we investigated the molecular mechanism for the recruitment of Polycomb repressive complex-2 (PRC2) and its accessory component, JARID2, to chromatin, which regulates methylation of lysine 27 of histone H3 (H3K27), during epithelial-mesenchymal transition (EMT) of cancer cells. The expression of MEG3 long noncoding RNA (lncRNA), which could interact with JARID2, was clearly increased during Transforming Growth Factor-beta (TGF-β)-induced EMT of human lung cancer cell lines...
November 16, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27845897/the-jazf1-suz12-fusion-protein-disrupts-prc2-complexes-and-impairs-chromatin-repression-during-human-endometrial-stromal-tumorogenesis
#3
Xianyong Ma, Jinglan Wang, Jianhui Wang, Charles X Ma, Xiaobin Gao, Vytas Patriub, Jeffrey L Sklar
The Polycomb repressive complex 2 (PRC2), which contains three core proteins EZH2, EED and SUZ12, controls chromatin compaction and transcription repression through trimethylation of lysine 27 on histone 3. The (7;17)(p15;q21) chromosomal translocation present in most cases of endometrial stromal sarcomas (ESSs) results in the in-frame fusion of the JAZF1 and SUZ12 genes. We have investigated whether and how the fusion protein JAZF1-SUZ12 functionally alters PRC2. We found that the fusion protein exists at high levels in ESS containing the t(7;17)...
November 10, 2016: Oncotarget
https://www.readbyqxmd.com/read/27830540/multifaceted-role-of-the-polycomb-group-gene-ezh2-in-hematological-malignancies
#4
REVIEW
Goro Sashida, Atsushi Iwama
Polycomb repressive complex (PRC) is a critical regulator of normal tissue homeostasis as well as tumorigenesis. EZH2, an enzymatic subunit of PRC2, is a histone H3K27 methyltransferase that functions in the regulation of gene silencing. EZH2 overexpression was first identified in prostate and breast cancers and is associated with poor clinical outcome. Subsequently, gain- and loss-of-function mutations of EZH2 have been identified in various tumors, including hematological malignancies, implicating EZH2 as either an oncogene or a tumor suppressor gene, depending on the cancer type...
November 9, 2016: International Journal of Hematology
https://www.readbyqxmd.com/read/27783950/roles-of-h3k27me2-and-h3k27me3-examined-during-fate-specification-of-embryonic-stem-cells
#5
Aster H Juan, Stan Wang, Kyung Dae Ko, Hossein Zare, Pei-Fang Tsai, Xuesong Feng, Karinna O Vivanco, Anthony M Ascoli, Gustavo Gutierrez-Cruz, Jordan Krebs, Simone Sidoli, Adam L Knight, Roger A Pedersen, Benjamin A Garcia, Rafael Casellas, Jizhong Zou, Vittorio Sartorelli
The polycomb repressive complex 2 (PRC2) methylates lysine 27 of histone H3 (H3K27) through its catalytic subunit Ezh2. PRC2-mediated di- and tri-methylation (H3K27me2/H3K27me3) have been interchangeably associated with gene repression. However, it remains unclear whether these two degrees of H3K27 methylation have different functions. In this study, we have generated isogenic mouse embryonic stem cells (ESCs) with a modified H3K27me2/H3K27me3 ratio. Our findings document dynamic developmental control in the genomic distribution of H3K27me2 and H3K27me3 at regulatory regions in ESCs...
October 25, 2016: Cell Reports
https://www.readbyqxmd.com/read/27758858/enhancer-of-zeste-homolog-2-inhibition-stimulates-bone-formation-and-mitigates-bone-loss-caused-by-ovariectomy-in-skeletally-mature-mice
#6
Amel Dudakovic, Emily T Camilleri, Scott M Riester, Christopher R Paradise, Martina Gluscevic, Thomas M O'Toole, Roman Thaler, Jared M Evans, Huihuang Yan, Malayannan Subramaniam, John R Hawse, Gary S Stein, Martin A Montecino, Meghan E McGee-Lawrence, Jennifer J Westendorf, Andre J van Wijnen
Perturbations in skeletal development and bone degeneration may result in reduced bone mass and quality, leading to greater fracture risk. Bone loss is mitigated by bone protective therapies, but there is a clinical need for new bone-anabolic agents. Previous work has demonstrated that Ezh2 (enhancer of zeste homolog 2), a histone 3 lysine 27 (H3K27) methyltransferase, suppressed differentiation of osteogenic progenitors. Here, we investigated whether inhibition of Ezh2 can be leveraged for bone stimulatory applications...
November 18, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27617932/regional-glutamine-deficiency-in-tumours-promotes-dedifferentiation-through-inhibition-of-histone%C3%A2-demethylation
#7
Min Pan, Michael A Reid, Xazmin H Lowman, Rajan P Kulkarni, Thai Q Tran, Xiaojing Liu, Ying Yang, Jenny E Hernandez-Davies, Kimberly K Rosales, Haiqing Li, Willy Hugo, Chunying Song, Xiangdong Xu, Dustin E Schones, David K Ann, Viviana Gradinaru, Roger S Lo, Jason W Locasale, Mei Kong
Poorly organized tumour vasculature often results in areas of limited nutrient supply and hypoxia. Despite our understanding of solid tumour responses to hypoxia, how nutrient deprivation regionally affects tumour growth and therapeutic response is poorly understood. Here, we show that the core region of solid tumours displayed glutamine deficiency compared with other amino acids. Low glutamine in tumour core regions led to dramatic histone hypermethylation due to decreased α-ketoglutarate levels, a key cofactor for the Jumonji-domain-containing histone demethylases...
October 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27578004/histone-h3k27-trimethylation-modulates-5-fluorouracil-resistance-by-inhibiting-pu-1-binding-to-the-dpyd-promoter
#8
Rentian Wu, Qian Nie, Erin E Tapper, Calvin R Jerde, Garrett S Dunlap, Shikshya Shrestha, Tarig A Elraiyah, Steven M Offer, Robert B Diasio
The antimetabolite 5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs. Dihydropyrimidine dehydrogenase (DPD) is a major determinant of 5-FU response and toxicity. Although DPYD variants may affect 5-FU metabolism, they do not completely explain the reported variability in DPD function or the resultant differences in treatment response. Here, we report that H3K27 trimethylation (H3K27me3) at the DPYD promoter regulated by Ezh2 and UTX suppresses DPYD expression by inhibiting transcription factor PU...
November 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27550047/long-non-coding-rna-hotair-expression-in-diffuse-large-b-cell-lymphoma-in-relation-to-polycomb-repressive-complex-pathway-proteins-and-h3k27-trimethylation
#9
Eun Ji Oh, Soo Hee Kim, Woo Ick Yang, Young Hyeh Ko, Sun Och Yoon
BACKGROUND: A long non-coding RNA hox transcript antisense intergenic RNA (HOTAIR) is involved in epigenetic regulation through chromatin remodeling by recruiting polycomb repressive complex 2 (PRC2) proteins (EZH2, SUZ12, and EED) that induce histone H3 trimethylation at lysine 27 (H3K27me3). Deregulation of c-MYC and interaction between c-MYC and EZH2 are well known in lymphomagenesis; however, little is known about the expression status of HOTAIR in diffuse large B-cell lymphomas (DLBCLs)...
September 2016: Journal of Pathology and Translational Medicine
https://www.readbyqxmd.com/read/27494834/gsk3%C3%AE-inactivation-promotes-the-oncogenic-functions-of-ezh2-and-enhances-methylation-of-h3k27-in-human-breast-cancers
#10
How-Wen Ko, Heng-Huan Lee, Longfei Huo, Weiya Xia, Cheng-Chieh Yang, Jennifer L Hsu, Long-Yuan Li, Chien-Chen Lai, Li-Chuan Chan, Chien-Chia Cheng, Adam M Labaff, Hsin-Wei Liao, Seung-Oe Lim, Chia-Wei Li, Yongkun Wei, Lei Nie, Hirohito Yamaguchi, Mien-Chie Hung
During the process of tumorigenesis, inactivation of tumor suppressors is a critical step. EZH2, a histone methyltransferase, promotes cell growth and migration through catalyzing trimethylation of histone H3 at Lys 27 (H3K27me3) and plays an important role in tumorigenesis. Its expression can be controlled by phosphorylation. However, the regulation of EZH2 activity by tumor suppressor kinase is not well understood. In this study, we show that glycogen synthase kinase 3 beta (GSK3β) negatively regulates H3K27 trimethylation...
August 2, 2016: Oncotarget
https://www.readbyqxmd.com/read/27490482/myc-activation-and-bcl2l11-silencing-by-a-tumour-virus-through-the-large-scale-reconfiguration-of-enhancer-promoter-hubs
#11
C David Wood, Hildegonda Veenstra, Sarika Khasnis, Andrea Gunnell, Helen M Webb, Claire Shannon-Lowe, Simon Andrews, Cameron S Osborne, Michelle J West
Lymphomagenesis in the presence of deregulated MYC requires suppression of MYC-driven apoptosis, often through downregulation of the pro-apoptotic BCL2L11 gene (Bim). Transcription factors (EBNAs) encoded by the lymphoma-associated Epstein-Barr virus (EBV) activate MYC and silence BCL2L11. We show that the EBNA2 transactivator activates multiple MYC enhancers and reconfigures the MYC locus to increase upstream and decrease downstream enhancer-promoter interactions. EBNA2 recruits the BRG1 ATPase of the SWI/SNF remodeller to MYC enhancers and BRG1 is required for enhancer-promoter interactions in EBV-infected cells...
2016: ELife
https://www.readbyqxmd.com/read/27468126/structure-activity-relationship-studies-for-enhancer-of-zeste-homologue-2-ezh2-and-enhancer-of-zeste-homologue-1-ezh1-inhibitors
#12
Xiaobao Yang, Fengling Li, Kyle D Konze, Jamel Meslamani, Anqi Ma, Peter J Brown, Ming-Ming Zhou, Cheryl H Arrowsmith, H Ümit Kaniskan, Masoud Vedadi, Jian Jin
EZH2 or EZH1 (enhancer of zeste homologue 2 or 1) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3 lysine 27 (H3K27). PRC2 hyperactivity and/or hypertrimethylation of H3K27 are associated with numerous human cancers, therefore inhibition of PRC2 complex has emerged as a promising therapeutic approach. Recent studies have shown that EZH2 and EZH1 are not functionally redundant and inhibition of both EZH2 and EZH1 is necessary to block the progression of certain cancers such as mixed-lineage leukemia (MLL)-rearranged leukemias...
August 25, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27439608/epigenetic-role-of-nuclear-s6k1-in-early-adipogenesis
#13
Sang Ah Yi, Jihoon Han, Jeung-Whan Han
S6K1 is a key regulator of cell growth, cell size, and metabolism. Although the role of cytosolic S6K1 in cellular processes is well established, the function of S6K1 in the nucleus remains poorly understood. Our recent study has revealed that S6K1 is translocated into the nucleus upon adipogenic stimulus where it directly binds to and phosphorylates H2B at serine 36. Such phosphorylation promotes EZH2 recruitment and subsequent histone H3K27 trimethylation on the promoter of its target genes including Wnt6, Wnt10a, and Wnt10b, leading to repression of their expression...
August 2016: BMB Reports
https://www.readbyqxmd.com/read/27431680/hypermethylation-of-cdh13-dkk3-and-foxl2-promoters-and-the-expression-of-ezh2-in-ovary-granulosa-cell-tumors
#14
Yanmei Xu, Xia Li, Hongtao Wang, Pengmu Xie, Xun Yan, Yu Bai, Tingguo Zhang
Aberrant epigenetic modification is associated with the development and progression of cancer. Hypermethylation of tumor suppressor gene promoters and cooperative histone modification have been considered to be the primary mechanisms of epigenetic modification. Ovary granulosa cell tumors (GCTs) are relatively rare, accounting for ~3% of all ovarian malignancies. The present study assessed hypermethylation of the cadherin 13 (CDH13), dickkopf WNT signaling pathway inhibitor 3 (DKK3) and forkhead box L2 (FOXL2) promoters in 30 GCT tissues and 30 healthy control tissues using methylation-specific polymerase chain reaction analysis...
September 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27424567/h3k4-acetylation-h3k9-acetylation-and-h3k27-methylation-in-breast-tumor-molecular-subtypes
#15
Gaëlle Judes, Aslihan Dagdemir, Seher Karsli-Ceppioglu, André Lebert, Maureen Echegut, Marjolaine Ngollo, Yves-Jean Bignon, Frédérique Penault-Llorca, Dominique Bernard-Gallon
AIM: Here, we investigated how the St Gallen breast molecular subtypes displayed distinct histone H3 profiles. PATIENTS & METHODS: 192 breast tumors divided into five St Gallen molecular subtypes (luminal A, luminal B HER2-, luminal B HER2+, HER2+ and basal-like) were evaluated for their histone H3 modifications on gene promoters. RESULTS: ANOVA analysis allowed to identify specific H3 signatures according to three groups of genes: hormonal receptor genes (ERS1, ERS2, PGR), genes modifying histones (EZH2, P300, SRC3) and tumor suppressor gene (BRCA1)...
July 2016: Epigenomics
https://www.readbyqxmd.com/read/27401345/the-loss-of-ezh2-drives-the-pathogenesis-of-myelofibrosis-and-sensitizes-tumor-initiating-cells-to-bromodomain-inhibition
#16
Goro Sashida, Changshan Wang, Takahisa Tomioka, Motohiko Oshima, Kazumasa Aoyama, Akinori Kanai, Makiko Mochizuki-Kashio, Hironori Harada, Kazuya Shimoda, Atsushi Iwama
EZH2 is a component of polycomb repressive complex 2 (PRC2) and functions as an H3K27 methyltransferase. Loss-of-function mutations in EZH2 are associated with poorer outcomes in patients with myeloproliferative neoplasms (MPNs), particularly those with primary myelofibrosis (MF [PMF]). To determine how EZH2 insufficiency is involved in the pathogenesis of PMF, we generated mice compound for an Ezh2 conditional deletion and activating mutation in JAK2 (JAK2V617F) present in patients with PMF. The deletion of Ezh2 in JAK2(V617F) mice markedly promoted the development of MF, indicating a tumor suppressor function for EZH2 in PMF...
July 25, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27380494/long-noncoding-rna-gihcg-promotes-hepatocellular-carcinoma-progression-through-epigenetically-regulating-mir-200b-a-429
#17
Cheng-Jun Sui, Yan-Ming Zhou, Wei-Feng Shen, Bing-Hua Dai, Jiong-Jiong Lu, Min-Feng Zhang, Jia-Mei Yang
: Long noncoding RNAs (lncRNAs) have been reported to play pivotal roles in a variety of cancers. However, lncRNAs involved in hepatocellular carcinoma (HCC) initiation and progression remain largely unclear. In this study, we identified an lncRNA gradually increased during hepatocarcinogenesis (lncRNA-GIHCG) using publicly available microarray data. Our results further revealed that GIHCG is upregulated in HCC tissues in comparison with adjacent non-tumor tissues. High GIHCG expression is correlated with large tumor size, microvascular invasion, advanced BCLC stage, and poor survival of HCC patients...
July 5, 2016: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/27378697/sustained-expression-of-fmr1-mrna-from-reactivated-fragile-x-syndrome-alleles-after-treatment-with-small-molecules-that-prevent-trimethylation-of-h3k27
#18
Daman Kumari, Karen Usdin
Expansion of a CGG-repeat tract in the 5'-untranslated region of the FMR1 gene to >200 repeats results in epigenetic silencing of the gene by a mechanism that is still unknown. FMR1 gene silencing results in fragile X syndrome (FXS), the most common heritable cause of intellectual disability. We have previously shown that reactivation of FMR1 gene in FXS cells with 5-azadeoxycytidine (AZA) leads to the transient recruitment of EZH2, the polycomb repressive complex 2 (PRC2) component responsible for H3K27 trimethylation, and that this recruitment depends on the presence of the FMR1 transcript...
July 4, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27367027/inflammatory-related-gene-ikk%C3%AE-ikk%C3%AE-ikk%C3%AE-cooperates-to-determine-liver-cancer-stem-cells-progression-by-altering-telomere-via-heterochromatin-protein-1-hotair-axis
#19
Jiahui An, Mengying Wu, Xiaoru Xin, Zhuojia Lin, Xiaonan Li, Qidi Zheng, Xin Gui, Tianming Li, Hu Pu, Haiyan Li, Dongdong Lu
Cancer stem cells are associated with tumor recurrence. IKK is a protein kinase that is composed of IKKα, IKKβ, IKKγ. Herein, we demonstrate that IKKα plus IKKβ promoted and IKKγ inhibited liver cancer stem cell growth in vitro and in vivo. Mechanistically, IKKα plus IKKβ enhanced and IKKγ inhibited the interplay among HP1α, HP1β and HP1γ that competes for the interaction among HP1α, SUZ12, HEZ2. Therefore, IKKα plus IKKβ inhibited and IKKγ enhanced the activity of H3K27 methyltransferase SUZ12 and EZH2, which methylates H3K27 immediately sites on HOTAIR promoter region...
June 29, 2016: Oncotarget
https://www.readbyqxmd.com/read/27272214/long-noncoding-rna-pvt1-promotes-cervical-cancer-progression-through-epigenetically-silencing-mir-200b
#20
Shaorong Zhang, Guanli Zhang, Jingying Liu
Long noncoding RNA PVT1 has been reported to be dysregulated and play vital roles in a variety of cancers. However, the functions and molecular mechanisms of PVT1 in cervical cancer remain unclear. The objective of this study was to investigate the expression, clinical significance, biological roles, and underlying functional mechanisms of PVT1 in cervical cancer. Our results revealed that PVT1 is upregulated in cervical cancer tissues. Enhanced expression of PVT1 is associated with larger tumor size, advanced International Federation of Gynecology and Obstetrics stage, and poor prognosis of cervical cancer patients...
August 2016: APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica
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