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https://www.readbyqxmd.com/read/28741798/novel-orally-bioavailable-ezh1-2-dual-inhibitors-with-greater-antitumor-efficacy-than-an-ezh2-selective-inhibitor
#1
REVIEW
Daisuke Honma, Osamu Kanno, Jun Watanabe, Junzo Kinoshita, Makoto Hirasawa, Emi Nosaka, Machiko Shiroishi, Takeshi Takizawa, Isao Yasumatsu, Takao Horiuchi, Akira Nakao, Keisuke Suzuki, Tomonori Yamasaki, Katsuyoshi Nakajima, Miho Hayakawa, Takanori Yamazaki, Ajay Singh Yadav, Nobuaki Adachi
Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 and represses gene expression to regulate cell proliferation and differentiation. Enhancer of zeste homolog 2 (EZH2) or its close homolog EZH1 function as catalytic subunits of PRC2, so there are two PRC2 complexes containing either EZH2 or EZH1. Tumorigenic functions of EZH2 and its synthetic lethality with some subunits of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes have been observed. However, little is known about the function of EZH1 in tumorigenesis...
July 25, 2017: Cancer Science
https://www.readbyqxmd.com/read/28722764/12-o-tetradecanoylphorbol-13-acetate-and-ezh2-inhibition-a-novel-approach-for-promoting-myogenic-differentiation-in-embryonal-rhabdomyosarcoma-cells
#2
Irene Marchesi, Luca Sanna, Milena Fais, Paolo Fiorentino Francesco, Antonio Giordano, Luigi Bagella
Rhabdomyosarcoma (RMS) is a soft tissue sarcoma that arises from muscle precursors affecting predominately children and young adults. It can be divided into two main classes: embryonal (eRMS) and alveolar rhabodomyosarcomas (aRMS). Despite the expression of early muscle specific genes, RMS cells fail to complete myogenesis even in differentiation conditions. We previously demonstrated that Enhancer Zeste of Homolog 2 (EZH2), the catalytic subunits of PRC2 complex, contributes to inhibit muscle differentiation in eRMS and its down-regulation causes a partial recovery of myogenesis...
July 19, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28700942/a-pml-slit-axis-controls-physiological-cell-migration-and-cancer-invasion-in-the-cns
#3
Valeria Amodeo, Deli A, Joanne Betts, Stefano Bartesaghi, Ying Zhang, Angela Richard-Londt, Matthew Ellis, Rozita Roshani, Mikaella Vouri, Sara Galavotti, Sarah Oberndorfer, Ana Paula Leite, Alan Mackay, Aikaterini Lampada, Eva Wessel Stratford, Ningning Li, David Dinsdale, David Grimwade, Chris Jones, Pierluigi Nicotera, David Michod, Sebastian Brandner, Paolo Salomoni
Cell migration through the brain parenchyma underpins neurogenesis and glioblastoma (GBM) development. Since GBM cells and neuroblasts use the same migratory routes, mechanisms underlying migration during neurogenesis and brain cancer pathogenesis may be similar. Here, we identify a common pathway controlling cell migration in normal and neoplastic cells in the CNS. The nuclear scaffold protein promyelocytic leukemia (PML), a regulator of forebrain development, promotes neural progenitor/stem cell (NPC) and neuroblast migration in the adult mouse brain...
July 11, 2017: Cell Reports
https://www.readbyqxmd.com/read/28692054/modeling-cancer-driver-events-in-vitro-using-barrier-bypass-clonal-expansion-assays-and-massively-parallel-sequencing
#4
H Huskova, M Ardin, A Weninger, K Vargova, S Barrin, S Villar, M Olivier, T Stopka, Z Herceg, M Hollstein, J Zavadil, M Korenjak
The information on candidate cancer driver alterations available from public databases is often descriptive and of limited mechanistic insight, which poses difficulties for reliable distinction between true driver and passenger events. To address this challenge, we performed in-depth analysis of whole-exome sequencing data from cell lines generated by a barrier bypass-clonal expansion (BBCE) protocol. The employed strategy is based on carcinogen-driven immortalization of primary mouse embryonic fibroblasts and recapitulates early steps of cell transformation...
July 10, 2017: Oncogene
https://www.readbyqxmd.com/read/28683324/doc1-dependent-recruitment-of-nurd-reveals-antagonism-with-swi-snf-during-epithelial-mesenchymal-transition-in-oral-cancer-cells
#5
Adone Mohd-Sarip, Miriam Teeuwssen, Alice G Bot, Maria J De Herdt, Stefan M Willems, Robert J Baatenburg de Jong, Leendert H J Looijenga, Diana Zatreanu, Karel Bezstarosti, Job van Riet, Edwin Oole, Wilfred F J van Ijcken, Harmen J G van de Werken, Jeroen A Demmers, Riccardo Fodde, C Peter Verrijzer
The Nucleosome Remodeling and Deacetylase (NURD) complex is a key regulator of cell differentiation that has also been implicated in tumorigenesis. Loss of the NURD subunit Deleted in Oral Cancer 1 (DOC1) is associated with human oral squamous cell carcinomas (OSCCs). Here, we show that restoration of DOC1 expression in OSCC cells leads to a reversal of epithelial-mesenchymal transition (EMT). This is caused by the DOC1-dependent targeting of NURD to repress key transcriptional regulators of EMT. NURD recruitment drives extensive epigenetic reprogramming, including eviction of the SWI/SNF remodeler, formation of inaccessible chromatin, H3K27 deacetylation, and binding of PRC2 and KDM1A, followed by H3K27 methylation and H3K4 demethylation...
July 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/28672805/epigenetic-regulation-of-the-epithelial-to-mesenchymal-transition-in-lung-cancer
#6
REVIEW
Joëlle Roche, Robert M Gemmill, Harry A Drabkin
Lung cancer is the leading cause of cancer deaths worldwide. It is an aggressive and devastating cancer because of metastasis triggered by enhanced migration and invasion, and resistance to cytotoxic chemotherapy. The epithelial to mesenchymal transition (EMT) is a fundamental developmental process that is reactivated in wound healing and a variety of diseases including cancer where it promotes migration/invasion and metastasis, resistance to treatment, and generation and maintenance of cancer stem cells. The induction of EMT is associated with reprogramming of the epigenome...
June 24, 2017: Cancers
https://www.readbyqxmd.com/read/28666925/ezh2-upregulation-correlates-with-tumor-invasiveness-proliferation-and-angiogenesis-in-human-pituitary-adenomas
#7
Bin Liu, Bo Pang, Qirui Wang, Shengji Yang, Taihong Gao, Qian Ding, Huajie Liu, Yihang Yang, Haitao Fan, Rui Zhang, Tao Xin, Guangming Xu, Qi Pang
Enhancer of zeste homolog 2 (EZH2) is a critical component of the polycomb repressive complex 2 (PRC2), which epigenetically represses genes involved in tumorigenesis and is highly expressed in tumors. However, no studies have investigated EZH2 expression and its clinical significance in human pituitary adenomas (PAs). Therefore, we examined the expression pattern of EZH2 in PAs and studied the correlations between protein expression and invasiveness, proliferation, angiogenesis, hormone functioning, and some other factors...
June 27, 2017: Human Pathology
https://www.readbyqxmd.com/read/28665819/targeting-ezh2-in-cancer-therapy
#8
Makoto Yamagishi, Kaoru Uchimaru
PURPOSE OF REVIEW: The present review introduces recent outstanding progress pertaining to Enhancer of zeste homolog 2 (EZH2), especially regarding its mode of action as a master regulator of chromatin, and provides molecular-based evidence for targeting EZH2 in cancer therapy. We discuss the active development of small molecules targeting the enzymatic activity of EZH2/polycomb repressive complex 2 (PRC2). RECENT FINDINGS: Genetic, transcriptional, and posttranscriptional dysregulation of EZH2 is frequently observed in many cancer types...
July 13, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/28664185/the-mir-125a-and-mir-320c-are-potential-tumor-suppressor-micrornas-epigenetically-silenced-by-the-polycomb-repressive-complex-2-in-multiple-myeloma
#9
Mohammad Alzrigat, Helena Jernberg-Wiklund
We have previously presented the histone methyltransferase enhancer of zeste homolog 2 (EZH2) of the polycomb repressive complex 2 (PRC2) as a potential therapeutic target in Multiple Myeloma (MM). In a recent article in Oncotarget by Alzrigat. et al. 2017, we have reported on the novel finding that EZH2 inhibition using the highly selective inhibitor of EZH2 enzymatic activity, UNC1999, reactivated the expression of microRNA genes previously reported to be underexpressed in MM. Among these, we have identified miR-125a-3p and miR-320c as potential tumor suppressor microRNAs as they were predicted to target MM-associated oncogenes; IRF-4, XBP-1 and BLIMP-1...
2017: RNA & Disease
https://www.readbyqxmd.com/read/28659173/long-noncoding-rna-mrccat1-promotes-metastasis-of-clear-cell-renal-cell-carcinoma-via-inhibiting-npr3-and-activating-p38-mapk-signaling
#10
Jia-Kuan Li, Cheng Chen, Jia-Yi Liu, Jia-Zi Shi, Shu-Peng Liu, Bing Liu, Deng-Shuang Wu, Zi-Yu Fang, Yi Bao, Ming-Ming Jiang, Ji-Hang Yuan, Le Qu, Lin-Hui Wang
BACKGROUND: Recent evidences showed that long noncoding RNAs (lncRNAs) are frequently dysregulated and play important roles in various cancers. Clear cell renal cell carcinoma (ccRCC) is one of the leading cause of cancer-related death, largely due to the metastasis of ccRCC. However, the clinical significances and roles of lncRNAs in metastatic ccRCC are still unknown. METHODS: lncRNA expression microarray analysis was performed to search the dysregulated lncRNA in metastatic ccRCC...
June 28, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28656062/c-myc-is-required-for-braf-v600e-induced-epigenetic-silencing-by-h3k27me3-in-tumorigenesis
#11
Yiping Qu, Qi Yang, Juan Liu, Bingyin Shi, Meiju Ji, Gang Li, Peng Hou
BRAF(V600E) mutation is frequently found in human cancers particularly thyroid cancer and melanoma, and is involved in the regulation of gene expression through activating MAPK/Erk signaling. Trimethylation of histone 3 lysine 27 (H3K27me3) is a critical epigenetic mark for the maintenance of gene silencing in tumorigenesis. However, molecular mechanism underlying the complex interplay between these two molecular events remains to be explored. In the present study, we conducted chromatin immunoprecipitation combined with next-generation sequencing (ChIP-Seq) and expression microarray analysis in NIH3T3 cells to explore the relationship between H3K27me3 and transcriptional regulation by BRAF(V600E) mutation...
2017: Theranostics
https://www.readbyqxmd.com/read/28647357/biophysical-characterization-of-histone-h3-3-k27m-point-mutation
#12
Szabolcs Hetey, Beáta Boros-Oláh, Tímea Kuik-Rózsa, Qiuzhen Li, Zsolt Karányi, Zoltán Szabó, Jason Roszik, Nikoletta Szalóki, György Vámosi, Katalin Tóth, Lóránt Székvölgyi
Lysine 27 to methionine (K27 M) mutation of the histone variant H3.3 drives the formation of an aggressive glioblastoma multiforme tumor in infants. Here we analyzed how the methionine substitution alters the stability of H3.3 nucleosomes in vitro and modifies its kinetic properties in live cells. We also determined whether the presence of mutant nucleosomes perturbed the mobility of the PRC2 subunit Ezh2 (enhancer-of-zeste homolog 2). We found that K27 M nucleosomes maintained the wild-type molecular architecture both at the level of bulk histones and single nucleosomes and followed similar diffusion kinetics to wild-type histones in live cells...
June 21, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28641467/green-tea-polyphenol-egcg-causes-anti-cancerous-epigenetic-modulations-in-acute-promyelocytic-leukemia-cells
#13
Veronika Borutinskaitė, Aida Virkšaitė, Giedrė Gudelytė, Rūta Navakauskienė
Green tea (Camellia sinensis) catechin epigallocatechin-3-gallate (EGCG) has been shown to possess diverse anti-cancerous properties. We demonstrated EGCG ability to inhibit acute promyelocytic leukemia (APL) cell proliferation and cause apoptosis. In addition, quantitative real-time polymerase chain reaction (RT-qPCR) analysis revealed elevated expression of genes associated with cell cycle arrest and differentiation (p27, PCAF, C/EBPα, and C/EBPɛ). Furthermore, EGCG caused anti-cancerous epigenetic changes: downregulation of epigenetic modifiers DNMT1, HDAC1, HDAC2, and G9a was observed by RT-qPCR analysis...
June 22, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28607149/polycomb-repressive-complex-2-in-an-autoinhibited-state
#14
Matthew Bratkowski, Xin Yang, Xin Liu
Polycomb-group proteins control many fundamental biological processes, such as anatomical development in mammals and vernalization in plants. Polycomb repressive complex 2 (PRC2) is responsible for methylation of histone H3 lysine 27 (H3K27), and trimethylated H3K27 (H3K27me3) is implicated in epigenetic gene silencing. Recent genomic, biochemical, and structural data indicate that PRC2 is broadly conserved from yeast to human in many aspects. Here, we determined the crystal structure of an apo PRC2 from the fungus Chaetomium thermophilum captured in a bona fide autoinhibited state, which represents a novel conformation of PRC2 associated with enzyme regulation in light of the basal and stimulated states that we reported previously...
June 12, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28604389/a-cullin-4b-ring-e3-ligase-complex-fine-tunes-pancreatic-%C3%AE-cell-paracrine-interactions
#15
Qing Li, Min Cui, Fan Yang, Na Li, Baichun Jiang, Zhen Yu, Daolai Zhang, Yijing Wang, Xibin Zhu, Huili Hu, Pei-Shan Li, Shang-Lei Ning, Si Wang, Haibo Qi, Hechen Song, Dongfang He, Amy Lin, Jingjing Zhang, Feng Liu, Jiajun Zhao, Ling Gao, Fan Yi, Tian Xue, Jin-Peng Sun, Yaoqin Gong, Xiao Yu
Somatostatin secreted by pancreatic δ cells mediates important paracrine interactions in Langerhans islets, including maintenance of glucose metabolism through the control of reciprocal insulin and glucagon secretion. Disruption of this circuit contributes to the development of diabetes. However, the precise mechanisms that control somatostatin secretion from islets remain elusive. Here, we found that a super-complex comprising the cullin 4B-RING E3 ligase (CRL4B) and polycomb repressive complex 2 (PRC2) epigenetically regulates somatostatin secretion in islets...
June 30, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28602614/mir-203-interplays-with-polycomb-repressive-complexes-to-regulate-the-proliferation-of-neural-stem-progenitor-cells
#16
Pei-Pei Liu, Gang-Bin Tang, Ya-Jie Xu, Yu-Qiang Zeng, Shuang-Feng Zhang, Hong-Zhen Du, Zhao-Qian Teng, Chang-Mei Liu
The polycomb repressive complexes 1 (PRC1) and 2 (PRC2) are two distinct polycomb group (PcG) proteins that maintain the stable silencing of specific sets of genes through chromatin modifications. Although the PRC2 component EZH2 has been known as an epigenetic regulator in promoting the proliferation of neural stem/progenitor cells (NSPCs), the regulatory network that controls this process remains largely unknown. Here we show that miR-203 is repressed by EZH2 in both embryonic and adult NSPCs. MiR-203 negatively regulates the proliferation of NSPCs...
July 11, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28596365/pcgf3-5-prc1-initiates-polycomb-recruitment-in-x-chromosome-inactivation
#17
Mafalda Almeida, Greta Pintacuda, Osamu Masui, Yoko Koseki, Michal Gdula, Andrea Cerase, David Brown, Arne Mould, Cassandravictoria Innocent, Manabu Nakayama, Lothar Schermelleh, Tatyana B Nesterova, Haruhiko Koseki, Neil Brockdorff
Recruitment of the Polycomb repressive complexes PRC1 and PRC2 by Xist RNA is an important paradigm for chromatin regulation by long noncoding RNAs. Here, we show that the noncanonical Polycomb group RING finger 3/5 (PCGF3/5)-PRC1 complex initiates recruitment of both PRC1 and PRC2 in response to Xist RNA expression. PCGF3/5-PRC1-mediated ubiquitylation of histone H2A signals recruitment of other noncanonical PRC1 complexes and of PRC2, the latter leading to deposition of histone H3 lysine 27 methylation chromosome-wide...
June 9, 2017: Science
https://www.readbyqxmd.com/read/28584023/notch-represses-transcription-by-prc2-recruitment-to-the-ternary-complex
#18
Xiaoqing Han, Prathibha Ranganathan, Christos Tzimas, Kelly L Weaver, Ke Jin, Luisana Astudillo, Wen Zhou, Xiaoxia Zhu, Bin Li, David J Robbins, Anthony J Capobianco
It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. This report reveals that the Notch ternary complex can direct the formation of a repressor complex to terminate gene expression of select target genes. Herein, it is demonstrated that p19Arf and Klf4 are transcriptionally repressed in a Notch-dependent manner...
June 5, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28577303/hhex-regulates-hematopoietic-stem-cell-self-renewal-and-stress-hematopoiesis-via-repression-of-cdkn2a
#19
Jacob T Jackson, Benjamin J Shields, Wei Shi, Ladina Di Rago, Donald Metcalf, Nicos A Nicola, Matthew P McCormack
The hematopoietically expressed homeobox transcription factor (Hhex) is important for the maturation of definitive hematopoietic progenitors and B-cells during development. We have recently shown that in adult hematopoiesis, Hhex is dispensable for maintenance of hematopoietic stem cells (HSCs) and myeloid lineages but essential for the commitment of common lymphoid progenitors (CLPs) to lymphoid lineages. Here, we show that during serial bone marrow transplantation, Hhex-deleted HSCs are progressively lost, revealing an intrinsic defect in HSC self-renewal...
August 2017: Stem Cells
https://www.readbyqxmd.com/read/28557790/long-non-coding-rna-profile-in-mantle-cell-lymphoma-identifies-a-functional-lncrna-ror1-as1-associated-with-ezh2-prc2-complex
#20
Guangzhen Hu, Shiv K Gupta, Tammy P Troska, Asha Nair, Mamta Gupta
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by rapid disease progression. The needs for new therapeutic strategies for MCL patients call for further understanding on the molecular mechanisms of pathogenesis of MCL. Recently, long noncoding RNAs (lncRNAs) have been recognized as key regulators of gene expression and disease development, however, the role of lncRNAs in non-Hodgkin lymphoma and specifically in MCL is still unknown. Next generation RNA-sequencing was carried out on MCL patient samples along with normal controls and data was analyzed...
May 17, 2017: Oncotarget
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