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Xiang Zhang, Xiao Zhang, Ting Wang, Lei Wang, Zhijun Tan, Wei Wei, Bo Yan, Jing Zhao, Kaichun Wu, Angang Yang, Rui Zhang, Lintao Jia
Overexpressed c-Myc and EZH2 usually mean high malignancy in cancers. Most of mortality from cancer is attributable to metastasis. MicroRNAs(miRNAs), like transcription factors, can regulate hundreds of genes. Here, we identify microRNA-26a (miR-26a) suppresses EZH2 and c-Myc by targeting EZH2 and CDK8 in Wnt pathway. MiR-26a is a well-known tumor-suppressive miRNA in multiple cancers, but how it is downregulated in hepatocellular carcinoma (HCC) is still unclear. Here, we disclose miR-26a is epigenetic silenced by a c-Myc-mediated PRC2-depandent way in HCC...
April 10, 2018: Cancer Letters
Shinichi Makita, Kensei Tobinai
No abstract text is available yet for this article.
April 9, 2018: Lancet Oncology
Antoine Italiano, Jean-Charles Soria, Maud Toulmonde, Jean-Marie Michot, Carlo Lucchesi, Andrea Varga, Jean-Michel Coindre, Stephen J Blakemore, Alicia Clawson, Benjamin Suttle, Alice A McDonald, Mark Woodruff, Scott Ribich, Eric Hedrick, Heike Keilhack, Blythe Thomson, Takashi Owa, Robert A Copeland, Peter T C Ho, Vincent Ribrag
BACKGROUND: Activating enhancer of zeste homolog 2 (EZH2) mutations or aberrations of the switch/sucrose non-fermentable (SWI/SNF) complex (eg, mutations or deletions of the subunits INI1 or SMARCA4) can lead to aberrant histone methylation, oncogenic transformation, and a proliferative dependency on EZH2 activity. In this first-in-human study, we aimed to investigate the safety, clinical activity, pharmacokinetics, and pharmacodynamics of tazemetostat, a first-in-class selective inhibitor of EZH2...
April 9, 2018: Lancet Oncology
Ji Hoon Phi, Ae Kyung Park, Semin Lee, Seung Ah Choi, In-Pyo Baek, Pora Kim, Eun-Hye Kim, Hee Chul Park, Byung Chul Kim, Jong Bhak, Sung-Hye Park, Ji Yeoun Lee, Kyu-Chang Wang, Dong-Seok Kim, Kyu Won Shim, Se Hoon Kim, Chae-Yong Kim, Seung-Ki Kim
Despite great advances in understanding of molecular pathogenesis and achievement of a high cure rate in medulloblastoma, recurrent medulloblastomas are still dismal. Additionally, misidentification of secondary malignancies due to histological ambiguity leads to misdiagnosis and eventually to inappropriate treatment. Nevertheless, the genomic characteristics of recurrent medulloblastomas are poorly understood, largely due to a lack of matched primary and recurrent tumor tissues. We performed a genomic analysis of recurrent tumors from 17 pediatric medulloblastoma patients...
April 11, 2018: Acta Neuropathologica
Barbara Fazi, Sabrina Garbo, Nicola Toschi, Annunziato Mangiola, Malinska Lombari, Daria Sicari, Cecilia Battistelli, Silvia Galardi, Alessandro Michienzi, Gianluca Trevisi, Rona Harari-Steinfeld, Carla Cicchini, Silvia Anna Ciafrè
The still largely obscure molecular events in the glioblastoma oncogenesis, a primary brain tumor characterized by an inevitably dismal prognosis, impel for investigation. The importance of Long noncoding RNAs as regulators of gene expression has recently become evident. Among them, H19 has a recognized oncogenic role in several types of human tumors and was shown to correlate to some oncogenic aspects of glioblastoma cells. Here we, hypothesyze that in glioblastoma H19 exerts its function through the interaction with the catalytic subunit of the PRC2 complex, EZH2...
March 20, 2018: Oncotarget
Yi Xu, Yue Yao, Xingming Jiang, Xiangyu Zhong, Zhidong Wang, Chunlong Li, Pengcheng Kang, Kaiming Leng, Daolin Ji, Zhenglong Li, Lining Huang, Wei Qin, Yunfu Cui
BACKGROUND: Accumulating evidence has indicated that long non-coding RNAs (lncRNAs) behave as a novel class of transcription products during multiple cancer processes. However, the mechanisms responsible for their alteration in cholangiocarcinoma (CCA) are not fully understood. METHODS: The expression of SPRY4-IT1 in CCA tissues and cell lines was determined by RT-qPCR, and the association between SPRY4-IT1 transcription and clinicopathologic features was analyzed...
April 11, 2018: Journal of Experimental & Clinical Cancer Research: CR
Ching-Ann Liu, Chia-Yu Chang, Kuo-Wei Hsueh, Hong-Lin Su, Tzyy-Wen Chiou, Shinn-Zong Lin, Horng-Jyh Harn
Malignant tumors of the central nervous system (CNS) are among cancers with the poorest prognosis, indicated by their association with tumors of high-level morbidity and mortality. Gliomas, the most common primary CNS tumors that arise from neuroglial stem or progenitor cells, have estimated annual incidence of 6.6 per 100,000 individuals in the USA, and 3.5 per 100,000 individuals in Taiwan. Tumor invasion and metastasis are the major contributors to the deaths in cancer patients. Therapeutic goals including cancer stem cells (CSC), phenotypic shifts, EZH2/AXL/TGF-β axis activation, miRNAs and exosomes are relevant to GBM metastasis to develop novel targeted therapeutics for GBM and other brain cancers...
April 8, 2018: International Journal of Molecular Sciences
Anan Fathy, Aziza E Abdelrahman
OBJECTIVE: Cervical cancer has an increasing incidence in developing countries with a predominance of squamous cell carcinoma. In this work, we aimed to analyze the role of EZH2, Endothelin-1, and CD34 as indicators of the aggressiveness in cervical squamous cell carcinoma. MATERIAL AND METHOD: Immunohistochemical expression of EZH2, Endothelin-1, and CD34 was studied in 54 paraffin-embedded tissue specimens of cervical squamous cell carcinoma. Their correlation to the clinicopathologic features and the potential angiogenic role were analyzed...
April 9, 2018: Türk Patoloji Dergisi
Xingli Zhang, Yan Wang, Jia Yuan, Ni Li, Siyu Pei, Jing Xu, Xuan Luo, Chaoming Mao, Junli Liu, Tao Yu, Shucheng Gan, Qianqian Zheng, Yinming Liang, Weixiang Guo, Ju Qiu, Gabriela Constantin, Jin Jin, Jun Qin, Yichuan Xiao
Histone 3 Lys27 (H3K27) trimethyltransferase Ezh2 is implicated in the pathogenesis of autoimmune inflammation. Nevertheless, the role of Ezh2 in macrophage/microglial activation remains to be defined. In this study, we identified that macrophage/microglial H3K27me3 or Ezh2, rather than functioning as a repressor, mediates toll-like receptor (TLR)-induced proinflammatory gene expression, and therefore Ezh2 depletion diminishes macrophage/microglial activation and attenuates the autoimmune inflammation in dextran sulfate sodium-induced colitis and experimental autoimmune encephalomyelitis...
April 6, 2018: Journal of Experimental Medicine
Guiju Tang, Jianfeng Guo, Yapei Zhu, Zaiju Huang, Ting Liu, Jing Cai, Lili Yu, Zehua Wang
Metformin has been used for the treatment of type II diabetes mellitus for decades. Recently, used of metformin in the therapy of diverse human cancer types has received widespread attention, while the underlying mechanisms have been not fully elucidated. In the current study, 5-ethynyl-20-deoxyuridine assay to detect cell proliferation, flow cytometry to detect apoptosis, scratch wound healing and Transwell migration assay to detect cell migration capacity. The current study reported that metformin inhibited cell proliferation and migration, and promoted apoptosis in ovarian cancer cells, particularly under normoglycemic conditions in vitro...
March 29, 2018: International Journal of Oncology
Paulo C M Urbano, Hans J P M Koenen, Irma Joosten, Xuehui He
A crucial issue for Treg-based immunotherapy is to maintain a bona fide Treg phenotype as well as suppressive function during and after ex vivo expansion. Several strategies have been applied to harness Treg lineage stability. For instance, CD28 superagonist stimulation in vitro , in the absence of CD3 ligation, is more efficient in promoting Treg proliferation, and prevention of pro-inflammatory cytokine expression, such as IL-17, as compared to CD3/CD28-stimulated Treg. Addition of the mTOR inhibitor rapamycin to Treg cultures enhances FOXP3 expression and Treg stability, but does impair proliferative capacity...
2018: Frontiers in Immunology
André Barbosa Ribeiro, Margarida Coucelo, Rita Tenreiro, Ana Teresa Simões, Gilberto Marques, Letícia Ribeiro, Emília Cortesão, Ana Bela Sarmento-Ribeiro
No abstract text is available yet for this article.
April 4, 2018: Leukemia & Lymphoma
Kunshou Zhu, Yujie Deng, Guoxing Weng, Dan Hu, Cheng Huang, Keitaro Matsumoto, Takeshi Nagayasu, Takehiko Koji, Xiongwei Zheng, Wenhui Jiang, Gen Lin, Yibin Cai, Guibin Weng, Xiaohui Chen
Smoking frequently leads to epigenetic alterations, including DNA methylation and histone modifications. The effect that smoking has on the DNA methylation levels at CCGG sites, the expression of trimethylation of histone H3 at lysine 27 (H3K27me3) and enhancer of zeste homolog 2 (EZH2), and their interactions in patients with non-small cell lung cancer (NSCLC) were analyzed. There were a total of 42 patients with NSCLC, 22 with adenocarcinomas and 20 with squamous cell carcinomas enrolled in the present study...
May 2018: Oncology Letters
Toshiya Inaba, Hiroaki Honda, Hirotaka Matsui
Since a report of some 50 years ago describing refractory anemia associated with group C monosomy, monosomy 7 (-7) and interstitial deletions of chromosome 7 [del(7q)] have been established as one of the most frequent chromosomal aberrations found in essentially all types of myeloid tumors regardless of patient age and disease etiology. In the last century, researchers sought recessive myeloid tumor-suppressor genes by attempting to determine commonly-deleted regions (CDRs) in del(7q) patients. However, these efforts were not successful...
April 3, 2018: Blood
Gundula Streubel, Ariane Watson, Sri Ganesh Jammula, Andrea Scelfo, Darren J Fitzpatrick, Giorgio Oliviero, Rachel McCole, Eric Conway, Eleanor Glancy, Gian Luca Negri, Eugene Dillon, Kieran Wynne, Diego Pasini, Nevan J Krogan, Adrian P Bracken, Gerard Cagney
The Polycomb repressor complex 2 (PRC2) is composed of the core subunits Ezh1/2, Suz12, and Eed, and it mediates all di- and tri-methylation of histone H3 at lysine 27 in higher eukaryotes. However, little is known about how the catalytic activity of PRC2 is regulated to demarcate H3K27me2 and H3K27me3 domains across the genome. To address this, we mapped the endogenous interactomes of Ezh2 and Suz12 in embryonic stem cells (ESCs), and we combined this with a functional screen for H3K27 methylation marks. We found that Nsd1-mediated H3K36me2 co-locates with H3K27me2, and its loss leads to genome-wide expansion of H3K27me3...
March 22, 2018: Molecular Cell
Karla M O'Neill, Rachelle E Irwin, Sarah-Jayne Mackin, Sara-Jayne Thursby, Avinash Thakur, Ciske Bertens, Laura Masala, Jayne E P Loughery, Darragh G McArt, Colum P Walsh
BACKGROUND: DNA methylation plays a vital role in the cell, but loss-of-function mutations of the maintenance methyltransferase DNMT1 in normal human cells are lethal, precluding target identification, and existing hypomorphic lines are tumour cells. We generated instead a hypomorphic series in normal hTERT-immortalised fibroblasts using stably integrated short hairpin RNA. RESULTS: Approximately two-thirds of sites showed demethylation as expected, with one-third showing hypermethylation, and targets were shared between the three independently derived lines...
March 29, 2018: Epigenetics & Chromatin
Takahiro Ito, Yee Voan Teo, Shane A Evans, Nicola Neretti, John M Sedivy
Polycomb group (PcG) factors maintain facultative heterochromatin and mediate many important developmental and differentiation processes. EZH2, a PcG histone H3 lysine-27 methyltransferase, is repressed in senescent cells. We show here that downregulation of EZH2 promotes senescence through two distinct mechanisms. First, depletion of EZH2 in proliferating cells rapidly initiates a DNA damage response prior to a reduction in the levels of H3K27me3 marks. Second, the eventual loss of H3K27me3 induces p16 (CDKN2A) gene expression independent of DNA damage and potently activates genes of the senescence-associated secretory phenotype (SASP)...
March 27, 2018: Cell Reports
Takeshi Fukumoto, Pyoung Hwa Park, Shuai Wu, Nail Fatkhutdinov, Sergey Karakashev, Timothy Nacarelli, Andrew V Kossenkov, David W Speicher, Stephanie Jean, Lin Zhang, Tian-Li Wang, Ie-Ming Shih, Jose R Conejo-Garcia, Benjamin G Bitler, Rugang Zhang
ARID1A, a subunit of the SWI/SNF complex, is among the most frequently mutated genes across cancer types. ARID1A is mutated in more than 50% of ovarian clear cell carcinomas (OCCCs), diseases that have no effective therapy. Here, we show that ARID1A mutation confers sensitivity to pan-HDAC inhibitors such as SAHA in ovarian cancers. This correlated with enhanced growth suppression induced by the inhibition of HDAC2 activity in ARID1A-mutated cells. HDAC2 interacts with EZH2 in an ARID1A status-dependent manner...
March 27, 2018: Cell Reports
Suresh Bugide, Michael R Green, Narendra Wajapeyee
Natural killer (NK) cell-mediated tumor cell eradication could inhibit tumor initiation and progression. However, the factors that regulate NK cell-mediated cancer cell eradication remain unclear. We determined that hepatocellular carcinoma (HCC) cells exhibit transcriptional down-regulation of NK group 2D (NKG2D) ligands and are largely resistant to NK cell-mediated eradication. Because the down-regulation of NKG2D ligands occurred at the transcriptional level, we tested 32 chemical inhibitors of epigenetic regulators for their ability to re-express NKG2D ligands and enhance HCC cell eradication by NK cells and found that Enhancer of zeste homolog 2 (EZH2) was a transcriptional repressor of NKG2D ligands...
March 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
Ali R Özeş, Nick Pulliam, Mustafa G Ertosun, Özlem Yılmaz, Jessica Tang, Ece Çopuroğlu, Daniela Matei, Osman N Özeş, Kenneth P Nephew
Polycomb repressive complex 2 (PRC2) member enhancer of zeste homolog 2 (EZH2) trimethylates histone H3 lysine 27 (H3K27me3), alters chromatin structure and contributes to epigenetic regulation of gene expression in normal and disease processes. Phosphorylation of EZH2 augmented EZH2 oncogenic activity in cancer but observations have been limited to threonine 350 (T350) and serine 21 (S21) residues by cyclin-dependent kinase 1 and protein kinase B, respectively. In addition, phosphorylation of the evolutionarily conserved T372 motif of EZH2 by p38 resulted in EZH2 interaction with Ying Yang 1 and promoted muscle stem cell differentiation...
March 26, 2018: Oncogene
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