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Lin Shan, Xing Zhou, Xinhua Liu, Yue Wang, Dongxue Su, Yongqiang Hou, Na Yu, Chao Yang, Beibei Liu, Jie Gao, Yang Duan, Jianguo Yang, Wanjin Li, Jing Liang, Luyang Sun, Kexin Chen, Chenghao Xuan, Lei Shi, Yan Wang, Yongfeng Shang
Although clinically associated with severe developmental defects, the biological function of FOXK2 remains poorly explored. Here we report that FOXK2 interacts with transcription corepressor complexes NCoR/SMRT, SIN3A, NuRD, and REST/CoREST to repress a cohort of genes including HIF1β and EZH2 and to regulate several signaling pathways including the hypoxic response. We show that FOXK2 inhibits the proliferation and invasion of breast cancer cells and suppresses the growth and metastasis of breast cancer. Interestingly, FOXK2 is transactivated by ERα and transrepressed via reciprocal successive feedback by HIF1β/EZH2...
October 14, 2016: Cancer Cell
Xingkang Jiang, Changwen Zhang, Shiyong Qi, Shanqi Guo, Yue Chen, E Du, Hongtuan Zhang, Xiaoming Wang, Ranlu Liu, Baomin Qiao, Kuo Yang, Zhihong Zhang, Yong Xu
Although we and other studies indicated ZNF217 expression was increased in prostate cancer (PCa), the factors mediating its misregulated expression and their oncogenic activity remain largely unexplored. Recent evidence demonstrated that ferroportin (FPN) reduction lead to decreased iron export and increased intercellular iron that consequently aggravates the oncogenic effects of iron. In the present study, ZNF217 was identified as a transcriptional repressor that inhibits FPN expression. Increased of ZNF217 expression led to decreased FPN concentration, coupled with resultant intracellular iron retention, increased iron-related cellular activities and enhanced tumor cell growth...
October 19, 2016: Oncotarget
Cortney L Lawrence, Albert S Baldwin
Enhancer of zeste homology 2 (EZH2) is the methyltransferase component of the polycomb repressive complex (PRC2) which represses gene transcription via histone H3 trimethylation at lysine 23 (H3K27me3). EZH2 activity has been linked with oncogenesis where it is thought to block expression of certain tumor suppressors. Relative to a role in cancer, EZH2 functions to promote self-renewal and has been shown to be important for the tumor-initiating cell (TIC) phenotype in breast cancer. Recently a non-canonical role for EZH2 has been identified where it promotes transcriptional activation of certain genes...
2016: PloS One
Bénazir Siddeek, Nadjem Lakhdari, Lilia Inoubli, Rachel Paul-Bellon, Véronique Isnard, Emmanuelle Thibault, André Bongain, Daniel Chevalier, Emanuela Repetto, Michele Trabucchi, Jean-François Michiels, Catherine Yzydorczyk, Umberto Simeoni, Michel Urtizberea, Claire Mauduit, Mohamed Benahmed
AIM: The Developmental Origin of Health and Disease refers to the concept that early exposure to toxicants or nutritional imbalances during perinatal life induces changes that enhance the risk of developing noncommunicable diseases in adulthood. Patients/materials & methods: An experimental model with an adult chronic germ cell phenotype resulting from exposure to a xenoestrogen was used. RESULTS: A reciprocal negative feedback loop involving decreased EZH2 protein level and increased miR-101 expression was identified...
October 20, 2016: Epigenomics
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 enhancer of zeste homolog 2 (Ezh2), a histone 3 lysine 27 (H3K27) methyltransferase, suppressed differentiation of osteogenic progenitors. Here, we investigated if inhibition of Ezh2 can be leveraged for bone stimulatory applications...
October 10, 2016: Journal of Biological Chemistry
Yuan-Yuan Zhang, Si-Han Huang, Hua-Rong Zhou, Cong-Jie Chen, Li-Hong Tian, Jian-Zhen Shen
HOX antisense intergenic RNA (HOTAIR), a long non-coding RNA, plays an important role in the development of many types of cancers. Its function in acute leukemia (AL), however, has not been examined. The present study investigated the role of HOTAIR and its downstream genes in AL, and determined whether it could act as a molecular marker for prediction of leukemia development and prognosis. Real-time quantitative PCR was used to examine the expression of each gene in the HOTAIR signaling pathway in AL patients...
October 4, 2016: Oncology Reports
Rishi G Vaswani, Victor S Gehling, Les A Dakin, Andrew Cook, Christopher G Nasveschuk, Martin Duplessis, Priyadarshini Iyer, Srividya Balasubramanian, Feng Zhao, Andrew C Good, Robert Campbell, Christina Lee, Nico Cantone, Richard T Cummings, Emmanuel Normant, Steven F Bellon, Brian K Albrecht, Jean-Christophe P Harmange, Patrick Trojer, James E Audia, Ying Zhang, Neil Justin, Shuyang Chen, Jon Wilson, Steve Gamblin
Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC50 = 0...
October 14, 2016: Journal of Medicinal Chemistry
Etienne Dardenne, Himisha Beltran, Matteo Benelli, Kaitlyn Gayvert, Adeline Berger, Loredana Puca, Joanna Cyrta, Andrea Sboner, Zohal Noorzad, Theresa MacDonald, Cynthia Cheung, Ka Shing Yuen, Dong Gao, Yu Chen, Martin Eilers, Juan-Miguel Mosquera, Brian D Robinson, Olivier Elemento, Mark A Rubin, Francesca Demichelis, David S Rickman
The transition from castration-resistant prostate adenocarcinoma (CRPC) to neuroendocrine prostate cancer (NEPC) has emerged as an important mechanism of treatment resistance. NEPC is associated with overexpression and gene amplification of MYCN (encoding N-Myc). N-Myc is an established oncogene in several rare pediatric tumors, but its role in prostate cancer progression is not well established. Integrating a genetically engineered mouse model and human prostate cancer transcriptome data, we show that N-Myc overexpression leads to the development of poorly differentiated, invasive prostate cancer that is molecularly similar to human NEPC...
October 10, 2016: Cancer Cell
N A Wijetunga, M Pascual, J Tozour, F Delahaye, M Alani, M Adeyeye, A W Wolkoff, A Verma, J M Greally
The predisposition of patients with Hepatitis C virus (HCV) infection to hepatocellular carcinoma (HCC) involves components of viral infection, inflammation and time. The development of multifocal, genetically distinct tumours is suggestive of a field defect affecting the entire liver. The molecular susceptibility mediating such a field defect is not understood. One potential mediator of long-term cellular reprogramming is heritable (epigenetic) regulation of transcription, exemplified by DNA methylation. We studied epigenetic and transcriptional changes in HCV-infected livers in comparison with control, uninfected livers and HCC, allowing us to identify pre-neoplastic epigenetic and transcriptional events...
October 10, 2016: Oncogene
Monica Cipollini, Stefano Landi, Federica Gemignani
BACKGROUND: Non-small-cell lung cancer (NSCLC) is an aggressive neoplasm with a poor survival and novel therapies are urgently needed. The study of deregulated micro-RNAs (dereg-miRs) could constitute a strategy helping to detect specific genes playing a relevant role in the disease. Thus, the oncoproteins encoded by these genes could be exploited as novel therapeutic targets to be inhibited by small molecules, aptamers, or monoclonal antibodies. METHODS: The present review is focused on candidate genes having convincing biological evidences to be both bona fide targets for dereg-miRs and playing a role in NSCLC progression...
October 6, 2016: Current Pharmaceutical Design
Zhongwei Li, Pingfu Hou, Dongmei Fan, Meichen Dong, Musong Ma, Hongyuan Li, Ruosi Yao, Yuxin Li, Guannan Wang, Pengyu Geng, Adhanom Mihretab, Dongxu Liu, Yu Zhang, Baiqu Huang, Jun Lu
EZH2 (the Enhancer of Zeste Homolog 2), as a key epigenetic regulator and EMT inducer, participates in a variety of cancer metastasis. EZH2 stability is regulated by several types of post-translational modifications (PTMs).The long non-coding RNAs (lncRNA) have been implicated to have critical roles in multiple carcinogenesis through a wide range of mechanisms, including modulating the stability of proteins. To date, whether the stability of EZH2 protein is regulated by lncRNAs remains unexplored. Here we report the discovery of ANCR modulating the stability of EZH2, and hence in the invasion and metastasis of breast cancer cells...
October 7, 2016: Cell Death and Differentiation
Imlimaong Aier, Pritish Kumar Varadwaj, Utkarsh Raj
Polycomb group (PcG) proteins have been observed to maintain the pattern of histone by methylation of the histone tail responsible for the gene expression in various cellular processes, of which enhancer of zeste homolog 2 (EZH2) acts as tumor suppressor. Overexpression of EZH2 results in hyper activation found in a variety of cancer. Point mutation on two important residues were induced and the results were compared between the wild type and mutant EZH2. The mutation of Y641 and A677 present in the active region of the protein alters the interaction of the top ranked compound with the newly modeled binding groove of the SET domain, giving a GLIDE score of -12...
October 7, 2016: Scientific Reports
(no author information available yet)
The GMR editorial staff was alerted about some manuscripts that were found to be substantially equal. The Publisher and Editor decided to retract these articles in accordance with the recommendations of the Committee on Publication Ethics (COPE). After a thorough investigation, we have strong reason to believe that the peer review process was failure and, after review and contacting the authors, the editors of Genetics and Molecular Research decided to retract these articles. The authors and their institutions were advised of this serious breach of ethics...
September 30, 2016: Genetics and Molecular Research: GMR
Yizhou Yao, Hao Hu, Yong Yang, Guoqiang Zhou, Zengfu Shang, Xiaodong Yang, Kang Sun, Shenghua Zhan, Zhengyuan Yu, Peiyao Li, Guofeng Pan, Liang Sun, Xinguo Zhu, Songbing He
Increasing evidence indicates that elevated expression of enhancer of zeste homolog 2 gene (EZH2) in many human malignant tumors acts a significant role in the oncogenic process. However, the underlying molecular mechanism is still unclarified. It is evident that apoptosis and autophagy of tumor cells is crucial for the tumorigenesis and progression of cancer, however, the exact role of EZH2 plays in apoptosis and autophagy has not been fully elucidated in colorectal cancer (CRC). Our previous study found that the expression level of EZH2 was higher in CRC tumor tissues than in the paired normal tissues using immunohistochemical analysis...
October 3, 2016: Genes
Fabio Bozzi, Silvia Brich, Gian Paolo Dagrada, Tiziana Negri, Elena Conca, Barbara Cortelazzi, Antonino Belfiore, Federica Perrone, Ambra Vittoria Gualeni, Annunziata Gloghini, Antonello Cabras, Monica Brenca, Roberta Maestro, Nadia Zaffaroni, Paolo Casali, Rossella Bertulli, Marcello Deraco, Silvana Pilotti
The aim of this study was to reconsider the biological characteristics of epithelioid malignant peritoneal mesothelioma (E-MpM) in the light of new concepts about epithelial mesenchymal transition and mesenchymal epithelial reverse transition (EMT/MErT) and the role of epigenetic reprogramming in this context. To this end we profiled surgical specimens and derived cells cultures by a number of complementary approaches i.e. immunohistochemistry, immunofluorescence, in situ hybridization, biochemistry, pluripotent stem cell arrays, treatments with cytokines, growth factors and specific inhibitors...
September 26, 2016: Oncotarget
Susan Azizmohammadi, Sima Azizmohammadi, Aghdas Safari, Maria Kaghazian, Mina Sadrkhanlo, Vahid Behnod, Mehri Seifoleslami
The investigation of specific genes will establish more useful biomarkers for accurate detection and management of gynecological cancers, especially patients with cervical cancer (CCP). The aim of this study was to evaluate the expression level of RIPK4 and EZH2 messenger RNA (RIPK4 and EZH2 mRNA) in CCP. Expression of RIPK4 and EZH2 in the tissues was determined by immunohistochemistry and qRT-PCR methods. Correlations of RIPK4 and EZH2 mRNA with clinical and pathological parameters were analyzed using the Fisher's exact test...
September 30, 2016: Oncology Research
N Hasegawa, M Oshima, G Sashida, H Matsui, S Koide, A Saraya, C Wang, T Muto, K Takane, A Kaneda, K Shimoda, C Nakaseko, K Yokote, A Iwama
Somatic inactivating mutations in epigenetic regulators are frequently found in combination in myelodysplastic syndrome (MDS). However, the mechanisms by which combinatory mutations in epigenetic regulators promote the development of MDS remain unknown. Here we performed epigenomic profiling of hematopoietic progenitors in MDS mice hypomorphic for Tet2 following the loss of the polycomb-group gene Ezh2 (Tet2(KD/KD)Ezh2(Δ/Δ)). Aberrant DNA methylation propagated in a sequential manner from a Tet2-insufficient state to advanced MDS with deletion of Ezh2...
October 21, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Kwaku Dad Abu-Bonsrah, Dongcheng Zhang, Donald F Newgreen
Chickens are an invaluable model for studying human diseases, physiology and especially development, but have lagged in genetic applications. With the advent of Programmable Engineered Nucleases, genetic manipulation has become efficient, specific and rapid. Here, we show that the CRISPR/Cas9 system can precisely edit the chicken genome. We generated HIRA, TYRP1, DICER, MBD3, EZH2, and 6 other gene knockouts in two chicken cell lines using the CRISPR/Cas9 system, with no off-target effects detected. We also showed that very large deletions (>75 kb) could be achieved...
October 3, 2016: Scientific Reports
Shi Chen, Jiang-Zhi Chen, Jia-Qiang Zhang, Hui-Xin Chen, Mao-Lin Yan, Long Huang, Yi-Feng Tian, Yan-Lin Chen, Yao-Dong Wang
The epithelial-mesenchymal transition (EMT) plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) development and progression. TWIST activated by intra-tumoral hypoxia functions to promote the EMT. We hypothesized that TWIST and the downstream gene pathway could mediate PDAC progression under hypoxia. Therefore, 90 PDAC tissue specimens were immunostained for TWIST and other proteins. Pancreatic cancer cell lines were used for in vitro experiments and nude mice were used to confirm the in vivo data...
September 28, 2016: Cancer Letters
Hussein M Atta, Ayman A Al-Hendy, Salama R Abdel Raheim, Hend Abdel-Ghany, Khalid A Nasif, Ahlam M Abdellah, Nagwa M Zenhom, Heba S Kamel
AIM OF THE STUDY: Adenovector encoding tissue plasminogen activator (tPA) was shown to reduce experimental peritoneal adhesion. We investigated the targeting potential of our modified adenovector, its ability to reduce adhesions and the epigenetic role of histone methyltransferase EZH2 in adhesion formation. MATERIALS AND METHODS: Control lacZ, nonmodified tPA or modified tPA vectors were instilled in the peritoneal cavity after injury in de novo adhesions or after lysis of adhesions in recurrent adhesions...
October 3, 2016: Journal of Investigative Surgery: the Official Journal of the Academy of Surgical Research
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