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Mateusz Bujko, Marcin M Machnicki, Emilia Grecka, Natalia Rusetska, Ewa Matyja, Paulina Kober, Tomasz Mandat, Małgorzata Rydzanicz, Rafał Płoski, Romuald Krajewski, Wieslaw Bonicki, Tomasz Stokłosa, Janusz A Siedlecki
BACKGROUND: Rhabdoid meningioma is rare aggressive meningioma histological subtype, which develops predominantly through progression from less malignant tumors. Due to a low incidence the biological background is unknown. The aim of this study was to profile somatic mutations in four meningioma samples from the same patient, derived previously from four subsequent tumor resections. CASE DESCRIPTION: 58-year-old woman suffering from recurrent meningioma progressing from atypical to rhabdoid subtype...
October 15, 2016: World Neurosurgery
Christine E Fuller
Over the past several decades, our understanding of malignant rhabdoid tumors (MRT) and the central nervous system equivalent atypical teratoid/rhabdoid tumor (ATRT) has undergone considerable refinement, particularly in terms of genetic characterization. MRT (both renal and extra-renal) and ATRT share phenotypic similarities and a common genetic signature, that being inactivating alterations of the SWI/SNF complex component SMARCB1 (or rarely SMARCA4). Unfortunately, a wide array of tumors bears significantly overlapping phenotypic characteristics to MRT/ATRT, posing a formidable diagnostic challenge...
August 31, 2016: Seminars in Diagnostic Pathology
Luca Tordella, Sadaf Khan, Anja Hohmeyer, Ana Banito, Sabrina Klotz, Selina Raguz, Nadine Martin, Gopuraja Dhamarlingam, Thomas Carroll, José Mario González Meljem, Sumit Deswal, Juan Pedro Martínez-Barbera, Ramón García-Escudero, Johannes Zuber, Lars Zender, Jesús Gil
Oncogene-induced senescence (OIS) is a potent tumor suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumors. ARID1B controls p16(INK4a) and p21(CIP1a) transcription but also regulates DNA damage, oxidative stress, and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence...
October 13, 2016: Genes & Development
Atsushi T Onaka, Naoko Toyofuku, Takahiro Inoue, Akiko K Okita, Minami Sagawa, Jie Su, Takeshi Shitanda, Rei Matsuyama, Faria Zafar, Tatsuro S Takahashi, Hisao Masukata, Takuro Nakagawa
Centromeres consist of DNA repeats in many eukaryotes. Non-allelic homologous recombination (HR) between them can result in gross chromosomal rearrangements (GCRs). In fission yeast, Rad51 suppresses isochromosome formation that occurs between inverted repeats in the centromere. However, how the HR enzyme prevents homology-mediated GCRs remains unclear. Here, we provide evidence that Rad51 with the aid of the Swi/Snf-type motor protein Rad54 promotes non-crossover recombination between centromere repeats to prevent isochromosome formation...
October 3, 2016: Nucleic Acids Research
Krzysztof Brzezinka, Simone Altmann, Hjördis Czesnick, Philippe Nicolas, Michal Gorka, Eileen Benke, Tina Kabelitz, Felix Jähne, Alexander Graf, Christian Kappel, Isabel Bäurle
Plants as sessile organisms can adapt to environmental stress to mitigate its adverse effects. As part of such adaptation they maintain an active memory of heat stress for several days that promotes a more efficient response to recurring stress. We show that this heat stress memory requires the activity of the FORGETTER1 (FGT1) locus, with fgt1 mutants displaying reduced maintenance of heat-induced gene expression. FGT1 encodes the Arabidopsis thaliana orthologue of Strawberry notch (Sno), and the protein globally associates with the promoter regions of actively expressed genes in a heat-dependent fashion...
September 28, 2016: ELife
N V Soshnikova, N E Vorob'eva, A A Kolacheva, D Y Gurskiy, R R Nigmatullina, Z A Zalyalova, S G Georgieva, M V Ugrumov
Parkinson's disease (PD) is the second most common neurodegenerative disorder and causes degeneration of dopaminergic neurons in the nigrostriatal system of the brain. PHF10 is one of the most important regulatory subunits of the SWI/SNF chromatin-remodeling protein complex, which controls the gene function and chromatin state in neurons. Two alternative RHF10 isoforms, PHF10-P and PHF10-S, replace each other in the complex to change the target gene pattern. Expression of the PHF10-P and PHF10-S transcripts in the nigrostriatal system and their ratio in blood lymphocytes were found to change in a mouse model of early clinical stage of PD as compared with control mice...
July 2016: Molekuliarnaia Biologiia
Eric Allemand, Michael P Myers, Jose Garcia-Bernardo, Annick Harel-Bellan, Adrian R Krainer, Christian Muchardt
Several studies propose an influence of chromatin on pre-mRNA splicing, but it is still unclear how widespread and how direct this phenomenon is. We find here that when assembled in vivo, the U2 snRNP co-purifies with a subset of chromatin-proteins, including histones and remodeling complexes like SWI/SNF. Yet, an unbiased RNAi screen revealed that the outcome of splicing is influenced by a much larger variety of chromatin factors not all associating with the spliceosome. The availability of this broad range of chromatin factors impacting splicing further unveiled their very context specific effect, resulting in either inclusion or skipping, depending on the exon under scrutiny...
September 2016: PLoS Genetics
S Zhang, B Zhou, L Wang, P Li, B D Bennett, R Snyder, S Garantziotis, D C Fargo, A D Cox, L Chen, G Hu
Epigenetic regulators are attractive targets for the development of new cancer therapies. Among them, the ATP-dependent chromatin remodeling complexes control the chromatin architecture and have important roles in gene regulation. They are often found to be mutated and de-regulated in cancers, but how they influence the cancer gene expression program during cancer initiation and progression is not fully understood. Here we show that the INO80 chromatin remodeling complex is required for oncogenic transcription and tumor growth in non-small-cell lung cancer (NSCLC)...
September 19, 2016: Oncogene
Vassilios Myrianthopoulos, Nicolas Gaboriaud-Kolar, Cynthia Tallant, Michelle-Lynn Hall, Stylianos Grigoriou, Peter Moore Brownlee, Oleg Fedorov, Catherine Rogers, David Heidenreich, Marek Wanior, Nikolaos Drosos, Nikitia Mexia, Pavel Savitsky, Tina Bagratuni, Efstathios Kastritis, Evangelos Terpos, Panagis Filippakopoulos, Susanne Müller, Alexios-Leandros Skaltsounis, Jessica Ann Downs, Stefan Knapp, Emmanuel Mikros
Bromodomains (BRDs) are epigenetic interaction domains currently recognized as emerging drug targets for development of anticancer or anti-inflammatory agents. In this study, development of a selective ligand of the fifth BRD of polybromo protein-1 (PB1(5)) related to switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes is presented. A compound collection was evaluated by consensus virtual screening and a hit was identified. The biophysical study of protein-ligand interactions was performed using X-ray crystallography and isothermal titration calorimetry...
October 13, 2016: Journal of Medicinal Chemistry
O A Romero, S Verdura, M Torres-Diz, A Gomez, S Moran, E Condom, M Esteller, A Villanueva, M Sanchez-Cespedes
Components of the SWI/SNF chromatin remodeling complex, including BRG1 (also SMARCA4), are inactivated in cancer. Among other functions, SWI/SNF orchestrates the response to retinoid acid (RA) and glucocorticoids (GC) involving downregulation of MYC. The epigenetic drugs SAHA and azacytidine, as well as RA and GC, are currently being used to treat some malignancies but their therapeutic potential in lung cancer is not well established. Here we aimed to determine the possible therapeutic effects of azacytidine and SAHA (A/S) alone or in combination with GC plus RA (GC/RA) in lung cancers with either BRG1 inactivation or MYC amplification...
September 5, 2016: Oncogene
Daniel Nettersheim, Sina Jostes, Martin Fabry, Friedemann Honecker, Valerie Schumacher, Jutta Kirfel, Glen Kristiansen, Hubert Schorle
In Western countries, the incidence of testicular germ cell cancers (GCC) is steadily rising over the last decades. Mostly, men between 20 and 40 years of age are affected. In general, patients suffering from GCCs are treated by orchiectomy and radio- or chemotherapy. Due to resistance mechanisms, intolerance to the therapy or denial of chemo- / radiotherapy by the patients, GCCs are still a lethal threat, highlighting the need for alternative treatment strategies.In this study, we revealed that germ cell cancer cell lines are highly sensitive to the histone deacetylase inhibitor romidepsin in vitro and in vivo, highlighting romidepsin as a potential therapeutic option for GCC patients...
August 27, 2016: Oncotarget
Mackenzie Coatham, Xiaodong Li, Anthony N Karnezis, Lien N Hoang, Basile Tessier-Cloutier, Bo Meng, Robert A Soslow, C Blake Gilks, David G Huntsman, Colin J R Stewart, Lynne M Postovit, Martin Köbel, Cheng-Han Lee
Dedifferentiated carcinoma of the endometrium or the ovary is an aggressive epithelial malignancy that comprises an endometrioid carcinoma together with an undifferentiated carcinoma. We recently reported that inactivation of BRG1 or INI1, core subunits of the switch/sucrose non-fermenting (SWI/SNF) complex, was the likely molecular event underlying dedifferentiation in about half of dedifferentiated carcinomas. In this study, we performed a genomic screen that included other members of the SWI/SNF complex to better delineate the molecular basis in the remainder of these tumours...
August 26, 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Thangavel Samikkannu, Venkata S R Atluri, Madhavan P N Nair
HIV infection and cocaine use have been identified as risk factors for triggering neuronal dysfunction. In the central nervous system (CNS), energy resource and metabolic function are regulated by astroglia. Glia is the major reservoir of HIV infection and disease progression in CNS. However, the role of cocaine in accelerating HIV associated energy deficit and its impact on neuronal dysfunction has not been elucidated yet. The aim of this study is to elucidate the molecular mechanism of HIV associated neuropathogenesis in cocaine abuse and how it accelerates the energy sensor AMPKs and its subsequent effect on mitochondrial oxidative phosphorylation (OXPHOS), BRSKs, CDC25B/C, MAP/Tau, Wee1 and epigenetics remodeling complex SWI/SNF...
2016: Scientific Reports
Toshiki Takenouchi, Hiroshi Yoshihashi, Yuri Sakaguchi, Tomoko Uehara, Masataka Honda, Takao Takahashi, Kenjiro Kosaki, Sahoko Miyama
Mutations in the BAF complex (mammalian SWI/SNF complex) are responsible for Coffin-Siris syndrome, which is characterized by developmental delay, distinctive facial features, hirsutism, and hypoplasia/aplasia of the fifth finger/fingernails. Hirschsprung disease is characterized by defective stem cells in the enteric neural system, and the involvement of multiple signaling cascades has been implicated. So far, the roles of the BAF complex in the genesis of Hirschsprung disease have remained unknown. Here, we document a patient with coarse facial features, postnatal growth failure, developmental delay, epilepsy, and hypoplasia of the corpus callosum and cerebellum but without a hypoplastic fifth finger/fingernail...
August 11, 2016: American Journal of Medical Genetics. Part A
Yutaka Takada, Akihisa Fukuda, Tsutomu Chiba, Hiroshi Seno
Brg1, a core subunit of the SWI/SNF chromatin remodeling complex, is essential for development and homeostasis of various organs. However, the functional role of Brg1 in intestinal development and homeostasis, and the underlying molecular mechanism, remain unknown. We found that deletion of Brg1 in the mouse intestine resulted in growth impairment and early death associated with abnormal crypt-villous formation, skewed differentiation into secretory lineage cells, markedly increased apoptosis, and stem cell loss in the duodenum...
October 1, 2016: Development
L Zhang, C W Jia, Z H Lu, J Chen
OBJECTIVE: To study ARID1A expression and its role in pancreatic neuroendocrine tumors. METHODS: 51 cases of pancreatic neuroendocrine tumors were collected from July 2003 to May 2012 from Peking Union Medical College Hospital.Eighteen normal pancreatic tissues were used as positive control. HE staining method was used to observe general clinicopathological features. ARID1A expression was detected immunohistochemically by EnVision method. The relationship between ARID1A expression and tumor grade and stage was analyzed...
August 8, 2016: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
Ramin Dubey, Andres M Lebensohn, Zahra Bahrami-Nejad, Caleb Marceau, Magali Champion, Olivier Gevaert, Branimir I Sikic, Jan E Carette, Rajat Rohatgi
Anthracyclines are among the most effective yet most toxic drugs used in the oncology clinic. The nucleosome-remodeling SWI/SNF complex, a potent tumor suppressor, is thought to promote sensitivity to anthracyclines by recruiting topoisomerase IIa (TOP2A) to DNA and increasing double-strand breaks. In this study, we discovered a novel mechanism through which SWI/SNF influences resistance to the widely used anthracycline doxorubicin based on the use of a forward genetic screen in haploid human cells, followed by a rigorous single and double-mutant epistasis analysis using CRISPR/Cas9-mediated engineering...
October 1, 2016: Cancer Research
Aarti Sethuraman, Martin Brown, Tiffany N Seagroves, Zhao-Hui Wu, Lawrence M Pfeffer, Meiyun Fan
BACKGROUND: While aberrant activation of the chromatin-remodeling SWI/SNF complexes has been associated with cancer development and progression, the role of each subunit in tumor cells is poorly defined. This study is aimed to characterize the role of SMARCE1/BAF57 in regulating metastasis of breast cancer cells. METHODS: Genetic approaches and chemical inhibitors were used to manipulate the activities of SMARCE1 and its downstream targets in multiple breast cancer cell lines...
2016: Breast Cancer Research: BCR
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
Maja Segedi, Laura N Anderson, Osvaldo Espin-Garcia, Ayelet Borgida, Teresa Bianco, Dangxiao Cheng, Zhuo Chen, Devalben Patel, M Catherine Brown, Wei Xu, David Reisman, Steven Gallinger, Michelle Cotterchio, Rayjean Hung, Geoffrey Liu, Sean P Cleary
Variant alleles of two promoter polymorphisms in the BRM gene (BRM-741, BRM-1321), create MEF2D transcription binding sites that lead to epigenetic silencing of BRM, the key catalytic component of the SWI/SNF chromatin remodeling complex. BRM suppression can be reversed pharmacologically.(1) Our group and others have reported associations with lung, head and neck, hepatocellular cancer risk,(1-3) and with lung and esophageal cancer prognosis (ASCO 2013; abstract 11057 & 4077). Herein, we assessed risk and survival associations with pancreatic cancer...
December 1, 2016: International Journal of Cancer. Journal International du Cancer
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