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EZH2

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https://www.readbyqxmd.com/read/28092155/discovery-of-first-in-class-potent-and-orally-bioavailable-eed-inhibitor-with-robust-anti-cancer-efficacy
#1
Ying Huang, Jeff Zhang, Zhengtian Yu, Hailong Zhang, Youzhen Wang, Andreas Lingel, Wei Qi, X Justin Gu, Kehao Zhao, Michael David Shultz, Long Wang, Xingnian Fu, Yongfeng Sun, Qiong Zhang, Xiangqing Jiang, Jiang-Wei Zhang, Chunye Zhang, Ling Li, Jue Zeng, Lijian Feng, Chao Zhang, Yueqin Liu, Man Zhang, Lijun Zhang, Mengxi Zhao, Zhenting Gao, Xianghui Liu, Douglas Fang, Haibing Guo, Yuan Mi, Tobias Gabriel, Michael P Dillon, Peter Atadja, Counde Oyang
Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit Polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (Tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective and orally bioavailable EED inhibitor EED226 (compound 43)...
January 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28089541/insulin-like-growth-factor-ii-mrna-binding-protein-3-imp3-is-a-marker-that-predict-presence-of-invasion-in-papillary-biliary-tumors
#2
Motoko Sasaki, Yasunori Sato
Biliary tumors showing intraductal papillary growth (Pap-BT) include intraductal papillary neoplasm of the bile duct (IPNB) and papillary cholangiocarcinoma (CC). A differential diagnosis between IPNB and papillary CC currently remains challenging. The aim of the present study is to identify histological features and immunohistochemical markers of malignant potential such as tumor invasion in Pap-BT. Subjects comprised 37 patients with Pap-BT (intrahepatic and perihilar (proximal), 27; 17 non-invasive and 10 invasive); distal 10, all invasive)...
January 13, 2017: Human Pathology
https://www.readbyqxmd.com/read/28088786/ezh2-inhibition-suppresses-endometrial-cancer-progression-via-mir-361-twist-axis
#3
Kei Ihira, Peixin Dong, Ying Xiong, Hidemichi Watari, Yosuke Konno, Sharon Jb Hanley, Masayuki Noguchi, Noriyuki Hirata, Futoshi Suizu, Takahiro Yamada, Masataka Kudo, Noriaki Sakuragi
EZH2 inhibition and reactivation of tumor suppressor microRNAs (miRNAs) represent attractive anti-cancer therapeutic strategies. We found that EZH2-suppressed let 7b and miR-361, two likely tumor suppressors, inhibited endometrial cancer (EC) cell proliferation and invasion, and abrogated cancer stem cell-like properties. In EC cells, EZH2 induced and functioned together with YY1 to epigenetically suppress miR-361, which upregulated Twist, a direct target of miR-361. Treating EC cells with GSK343, a specific EZH2 inhibitor, mimicked the effects of siRNA-mediated EZH2 knockdown, upregulating miR-361 and downregulating Twist expression...
January 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28078190/loss-of-quiescence-and-self-renewal-capacity-of-hematopoietic-stem-cell-in-an-in-vitro-leukemic-niche
#4
Natalia-Del Pilar Vanegas, Jean-Paul Vernot
BACKGROUND: Leukemic and mesenchymal stem cells interact in the leukemic microenvironment and affect each other differently. This interplay has also important implications for the hematopoietic stem cell (HSC) biology and function. This study evaluated human HSC self-renewal potential and quiescence in an in vitro leukemic niche without leukemic cells. METHODS: A leukemic niche was established by co-culturing mesenchymal stem cells with a fresh conditioned medium obtained from a leukemic (REH) cell line...
2017: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/28072972/-clinicopathologic-features-of-adenoid-cystic-carcinoma-of-breast
#5
S P Guo, Q L Li, Y M Wang, K X Zeng, Y Liu, W N Xu, X M Zhang
Objective: To investigate the clinicopathologic features and grading of adenoid cystic carcinoma (ACC) of the breast. Methods: Sixteen cases of ACC of the breast were analyzed and graded according to the previous report. Immunohistochemical (IHC) staining was used to detect the immunophenotype, Ki-67 proliferative index and expression of EZH2, and the association with tumor grade and outcome was analyzed. Results: Of the 16 cases, 11 were grade Ⅰ, with the epithelial and myoepithelial cells being arranged into tubular and cribriform structure with no solid component; three were grade Ⅱ, which were composed of mixed tubular, cribriform and solid component (<30%); and two were grade Ⅲ, which showed mainly solid component (>90%) and the tumor cells showed basaloid features with scanty cytoplasm and hyperchromatic nuclei, and mitotic count was>5/10 HPF...
January 8, 2017: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
https://www.readbyqxmd.com/read/28069878/malat1-is-associated-with-poor-response-to-oxaliplatin-based-chemotherapy-in-colorectal-cancer-patients-and-promotes-chemoresistance-through-ezh2
#6
Peilong Li, Xin Zhang, Haiyan Wang, Lili Wang, Tong Liu, Lutao Du, Yongmei Yang, Chuanxin Wang
A major reason for oxaliplatin chemoresistance in colorectal cancer (CRC) is the acquisition of epithelial-mesenchymal transition (EMT) in cancer cells. The long non-coding RNA, MALAT1, is a highly conserved nuclear ncRNA and a key regulator of metastasis development in several cancers. However, its role in oxaliplatin-induced metastasis and chemo-resistance is not well known. In this study, we aim to investigate the prognostic and therapeutic role of MALAT1 in CRC patients receiving oxaliplatin-based therapy, and further explore the potential transcriptional regulation through interaction with EZH2 based on the established HT29 oxaliplatin-resistant cells...
January 9, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28069000/long-non-coding-rna-tug1-is-involved-in-cell-growth-and-chemoresistance-of-small-cell-lung-cancer-by-regulating-limk2b-via-ezh2
#7
Yuchun Niu, Feng Ma, Weimei Huang, Shun Fang, Man Li, Ting Wei, Linlang Guo
BACKGROUND: Taurine upregulated gene1 (TUG1) as a 7.1-kb lncRNA, has been shown to play an oncogenic role in various cancers. However, the biological functions of lncRNA TUG1 in small cell lung cancer (SCLC) remain unknown. The aim of this study is to explore the roles of TUG1 in cell growth and chemoresistance of SCLC and its possible molecular mechanism. METHODS: The expression of TUG1 in thirty-three cases of SCLC tissues and SCLC cell line were examined by quantitative RT-PCR (qRT-PCR)...
January 9, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28068325/trim28-interacts-with-ezh2-and-swi-snf-to-activate-genes-that-promote-mammosphere-formation
#8
J Li, Y Xi, W Li, R L McCarthy, S A Stratton, W Zou, W Li, S Y Dent, A K Jain, M C Barton
Histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2) is generally associated with H3K27 methylation and gene silencing, as a member of the polycomb repressor 2 (PRC2) complex. Immunoprecipitation and mass spectrometry of the EZH2-protein interactome in estrogen receptor positive, breast cancer-derived MCF7 cells revealed EZH2 interactions with subunits of chromatin remodeler SWI/SNF complex and TRIM28, which formed a complex with EZH2 distinct from PRC2. Unexpectedly, transcriptome profiling showed that EZH2 primarily activates, rather than represses, transcription in MCF7 cells and with TRIM28 co-regulates a set of genes associated with stem cell maintenance and poor survival of breast cancer patients...
January 9, 2017: Oncogene
https://www.readbyqxmd.com/read/28067271/praja1-e3-ubiquitin-ligase-promotes-skeletal-myogenesis-through-degradation-of-ezh2-upon-p38%C3%AE-activation
#9
Silvia Consalvi, Arianna Brancaccio, Alessandra Dall'Agnese, Pier Lorenzo Puri, Daniela Palacios
Polycomb proteins are critical chromatin modifiers that regulate stem cell differentiation via transcriptional repression. In skeletal muscle progenitors Enhancer of zeste homologue 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), contributes to maintain the chromatin of muscle genes in a repressive conformation, whereas its down-regulation allows the progression through the myogenic programme. Here, we show that p38α kinase promotes EZH2 degradation in differentiating muscle cells through phosphorylation of threonine 372...
January 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28062277/circ100284-via-mir-217-regulation-of-ezh2-is-involved-in-the-arsenite-accelerated-cell-cycle-of-human-keratinocytes-in-carcinogenesis
#10
Junchao Xue, Yang Liu, Fei Luo, Xiaolin Lu, Hui Xu, Xinlu Liu, Lu Lu, Qianlei Yang, Chao Chen, Weimin Fan, Qizhan Liu
Circular RNAs (circRNAs), a class of noncoding RNAs generated from pre-mRNAs, participate in regulation of genes. The mechanism for regulation, however, is unknown. Here, to determine if, in human keratinocyte (HaCaT) cells, circular RNAs are involved in arsenite-induced acceleration of the cell cycle, a circRNA microarray was performed to analyze the variability of circRNAs in arsenite-treated HaCaT (As-HaCaT) cells and in arsenite-transformed (T-HaCaT) cells in comparison to control HaCaT cells. Among the circRNAs up-regulated in both As-HaCaT cells and T-HaCaT cells, hsa:circRNA_100284 (circ100284) had the greatest increase and was chosen for further research...
January 3, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28060766/opposing-roles-of-pik3ca-gene-alterations-to-ezh2-signaling-in-non-muscle-invasive-bladder-cancer
#11
Cristina Segovia, Mónica Martínez-Fernández, Marta Dueñas, Carolina Rubio, Fernando F López-Calderón, Clotilde Costa, Cristina Saiz-Ladera, María Fernández-Grajera, José Duarte, Huberto García Muñoz, Federico de la Rosa, Felipe Villacampa, Daniel Castellano, Jesús M Paramio
The high rates of tumor recurrence and progression represent a major clinical problem in non-muscle invasive bladder cancer. Previous data showed that EZH2-dependent signaling mediates these processes, whereas the frequent alterations of PIK3CA gene (copy gains and mutations) are predictive of reduced recurrence. Here we show, using clinical samples and bladder cancer cell lines, a functional interaction between EZH2- and PIK3CA-dependent signaling pathways. PIK3CA alterations mediated, on the one hand, the increased expression of two miRNAs, miR-101 and miR-138, which posttranscriptionally downregulate EZH2 expression...
January 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28059767/rb1-and-trp53-cooperate-to-suppress-prostate-cancer-lineage-plasticity-metastasis-and-antiandrogen-resistance
#12
Sheng Yu Ku, Spencer Rosario, Yanqing Wang, Ping Mu, Mukund Seshadri, Zachary W Goodrich, Maxwell M Goodrich, David P Labbé, Eduardo Cortes Gomez, Jianmin Wang, Henry W Long, Bo Xu, Myles Brown, Massimo Loda, Charles L Sawyers, Leigh Ellis, David W Goodrich
Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting that lineage plasticity facilitates therapeutic resistance. The mechanisms underlying prostate cancer lineage plasticity are incompletely understood. Studying mouse models, we demonstrate that Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation. Additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicates that mouse tumors resemble human prostate cancer neuroendocrine variants; both mouse and human tumors exhibit increased expression of epigenetic reprogramming factors such as Ezh2 and Sox2...
January 6, 2017: Science
https://www.readbyqxmd.com/read/28052011/ezh2-inhibition-in-multiple-myeloma-downregulates-myeloma-associated-oncogenes-and-upregulates-micrornas-with-potential-tumor-suppressor-functions
#13
Mohammad Alzrigat, Alba Atienza Párraga, Prasoon Agarwal, Hadil Zureigat, Anders Österborg, Hareth Nahi, Anqi Ma, Jian Jin, Kenneth Nilsson, Fredrik Öberg, Antonia Kalushkova, Helena Jernberg-Wiklund
Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM...
December 30, 2016: Oncotarget
https://www.readbyqxmd.com/read/28049658/stage-and-subunit-specific-functions-of-polycomb-repressive-complex-2-in-bladder-urothelial-formation-and-regeneration
#14
Chunming Guo, Zarine R Balsara, Warren G Hill, Xue Li
Urothelium is the protective lining of the urinary tract. The mechanisms underlying urothelial formation and maintenance are largely unknown. Here, we report the stage-specific roles of PRC2 epigenetic regulators in embryonic and adult urothelial progenitors. Without Eed, the obligatory subunit of PRC2, embryonic urothelial progenitors demonstrate reduced proliferation with concomitant dysregulation of genes including Cdkn2a(p16), Cdkn2b(p15) and Shh. These mutants display premature differentiation of Keratin 5-positive (Krt5(+)) basal cells and ectopic expression of squamous-like differentiation markers...
January 3, 2017: Development
https://www.readbyqxmd.com/read/28044469/epigenetic-silencing-and-activation-of-transcription-influence-on-the-radiation-sensitivity-of-glioma-cell-lines
#15
A Sak, D Kübler, K Bannik, M Groneberg, S Strunz, R Kriehuber, M Stuschke
PURPOSE: To uncover the role of EZH2 and its opponent ASHL2, a polycomb and trithorax group protein, respectively on the radioresponsiveness of glioma cell lines. MATERIAL AND METHODS: Expression of EZH2 and ASHL2 was inhibited by siRNA in glioma cell lines. The effect on histone methylation, gene expression, DNA damage repair signaling, cell cycle checkpoints, apoptosis and tumor control were evaluated. RESULTS: Inhibition of EZH2 (EZH2i) led to a transcriptional dysregulation with upregulation of 544 and downregulation of 445 genes...
January 3, 2017: International Journal of Radiation Biology
https://www.readbyqxmd.com/read/28042859/a-novel-role-of-silibinin-as-a-putative-epigenetic-modulator-in-human-prostate-carcinoma
#16
Ioannis Anestopoulos, Aristeidis P Sfakianos, Rodrigo Franco, Katerina Chlichlia, Mihalis I Panayiotidis, David J Kroll, Aglaia Pappa
Silibinin, extracted from milk thistle (Silybum marianum L.), has exhibited considerable preclinical activity against prostate carcinoma. Its antitumor and chemopreventive activities have been associated with diverse effects on cell cycle, apoptosis, and receptor-dependent mitogenic signaling pathways. Here we hypothesized that silibinin's pleiotropic effects may reflect its interference with epigenetic mechanisms in human prostate cancer cells. More specifically, we have demonstrated that silibinin reduces gene expression levels of the Polycomb Repressive Complex 2 (PRC2) members Enhancer of Zeste Homolog 2 (EZH2), Suppressor of Zeste Homolog 12 (SUZ12), and Embryonic Ectoderm Development (EED) in DU145 and PC3 human prostate cancer cells, as evidenced by Real Time Polymerase Chain Reaction (RT-PCR)...
December 31, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28034643/the-long-non-coding-rna-neat1-interacted-with-mir-101-modulates-breast-cancer-growth-by-targeting-ezh2
#17
Ke Qian, Gao Liu, Zhonghua Tang, Yibo Hu, Yu Fang, Zonglin Chen, Xundi Xu
Nuclear enriched abundant transcript 1 (NEAT1), an important cancer-associated long non-coding RNA (lncRNA), contributes to the development and progression of several cancers. An increased expression of NEAT1 was observed in cancers including bladder cancer, lung cancer and breast cancer (BC). However, the exact effect of NEAT1 in BC progression and the underlying molecular mechanisms are still unknown up to now. Here, we investigated the detailed role of NEAT1 in human BC cell lines and clinical tumor samples in order to validate the function of this molecule...
December 26, 2016: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28030797/galeterone-and-its-analogs-inhibit-mnk-eif4e-axis-synergize-with-gemcitabine-impede-pancreatic-cancer-cell-migration-invasion-and-proliferation-and-inhibit-tumor-growth-in-mice
#18
Andrew K Kwegyir-Afful, Francis N Murigi, Puranik Purushottamachar, Vidya P Ramamurthy, Marlena S Martin, Vincent C O Njar
Survival rate for pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is poor, with about 80% of patients presenting with the metastatic disease. Gemcitabine, the standard chemotherapeutic agent for locally advanced and metastatic PDAC has limited efficacy, attributed to innate/acquired resistance and activation of pro-survival pathways. The Mnk1/2-eIF4E and NF-κB signaling pathways are implicated in PDAC disease progression/metastasis and also associated with gemcitabine-induced resistance in PDAC...
December 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/28028462/network-based-analysis-of-differentially-expressed-genes-in-cerebrospinal-fluid-csf-and-blood-reveals-new-candidate-genes-for-multiple-sclerosis
#19
Nahid Safari-Alighiarloo, Mostafa Rezaei-Tavirani, Mohammad Taghizadeh, Seyyed Mohammad Tabatabaei, Saeed Namaki
BACKGROUND: The involvement of multiple genes and missing heritability, which are dominant in complex diseases such as multiple sclerosis (MS), entail using network biology to better elucidate their molecular basis and genetic factors. We therefore aimed to integrate interactome (protein-protein interaction (PPI)) and transcriptomes data to construct and analyze PPI networks for MS disease. METHODS: Gene expression profiles in paired cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) samples from MS patients, sampled in relapse or remission and controls, were analyzed...
2016: PeerJ
https://www.readbyqxmd.com/read/28028029/genetic-basis-and-molecular-pathophysiology-of-classical-myeloproliferative-neoplasms
#20
William Vainchenker, Robert Kralovics
The genetic landscape of classical myeloproliferative neoplasm (MPN) is in large part elucidated. The MPN restricted driver mutations including those in JAK2, calreticulin (CALR) and MPL abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors, more particularly the STATs. The most frequent mutation, JAK2V617F, activates the three main myeloid cytokine receptors (EPOR, G-CSFR and MPL) whereas CALR or MPL mutants are restricted to MPL activation. This explains why JAK2V617F is associated with polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) whereas CALR and MPL mutants are found in ET and PMF...
December 27, 2016: Blood
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