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https://www.readbyqxmd.com/read/27890923/the-epigenetic-landscape-of-renal-cancer
#1
REVIEW
Mark R Morris, Farida Latif
The majority of kidney cancers are associated with mutations in the von Hippel-Lindau gene and a small proportion are associated with infrequent mutations in other well characterized tumour-suppressor genes. In the past 15 years, efforts to uncover other key genes involved in renal cancer have identified many genes that are dysregulated or silenced via epigenetic mechanisms, mainly through methylation of promoter CpG islands or dysregulation of specific microRNAs. In addition, the advent of next-generation sequencing has led to the identification of several novel genes that are mutated in renal cancer, such as PBRM1, BAP1 and SETD2, which are all involved in histone modification and nucleosome and chromatin remodelling...
November 28, 2016: Nature Reviews. Nephrology
https://www.readbyqxmd.com/read/27846294/identification-and-verification-of-potential-therapeutic-target-genes-in-berberine-treated-zucker-diabetic-fatty-rats-through-bioinformatics-analysis
#2
Yang Sheng Wu, Yi-Tao Chen, Yu-Ting Bao, Zhe-Ming Li, Xiao-Jie Zhou, Jia-Na He, Shi-Jie Dai, Chang Yu Li
BACKGROUND: Berberine is used to treat diabetes and dyslipidemia. However, the effect of berberine on specific diabetes treatment targets is unknown. In the current study, we investigated the effect of berberine on the random plasma glucose, glycated hemoglobin (HbA1C), AST, ALT, BUN and CREA levels of Zucker diabetic fatty (ZDF) rats, and we identified and verified the importance of potential therapeutic target genes to provide molecular information for further investigation of the mechanisms underlying the anti-diabetic effects of berberine...
2016: PloS One
https://www.readbyqxmd.com/read/27834213/high-density-array-cgh-with-targeted-ngs-unmask-multiple-noncontiguous-minute-deletions-on-chromosome-3p21-in-mesothelioma
#3
Yoshie Yoshikawa, Mitsuru Emi, Tomoko Hashimoto-Tamaoki, Masaki Ohmuraya, Ayuko Sato, Tohru Tsujimura, Seiki Hasegawa, Takashi Nakano, Masaki Nasu, Sandra Pastorino, Agata Szymiczek, Angela Bononi, Mika Tanji, Ian Pagano, Giovanni Gaudino, Andrea Napolitano, Chandra Goparaju, Harvey I Pass, Haining Yang, Michele Carbone
We used a custom-made comparative genomic hybridization array (aCGH; average probe interval 254 bp) to screen 33 malignant mesothelioma (MM) biopsies for somatic copy number loss throughout the 3p21 region (10.7 Mb) that harbors 251 genes, including BRCA1 (breast cancer 1)-associated protein 1 (BAP1), the most commonly mutated gene in MM. We identified frequent minute biallelic deletions (<3 kb) in 46 of 251 genes: four were cancer-associated genes: SETD2 (SET domain-containing protein 2) (7 of 33), BAP1 (8 of 33), PBRM1 (polybromo 1) (3 of 33), and SMARCC1 (switch/sucrose nonfermentable- SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily c, member 1) (2 of 33)...
November 22, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27813512/genomic-profiling-of-malignant-peritoneal-mesothelioma-reveals-recurrent-alterations-in-epigenetic-regulatory-genes-bap1-setd2-and-ddx3x
#4
Nancy M Joseph, Yunn-Yi Chen, Anthony Nasr, Iwei Yeh, Eric Talevich, Courtney Onodera, Boris C Bastian, Joseph T Rabban, Karuna Garg, Charles Zaloudek, David A Solomon
Malignant mesothelioma is a rare cancer that arises from the mesothelial cells that line the pleural cavity and less commonly from the peritoneal lining of the abdomen and pelvis. Most pleural mesotheliomas arise in patients with a history of asbestos exposure, whereas the association of peritoneal mesotheliomas with exposure to asbestos and other potential carcinogens is less clear, suggesting that the genetic alterations that drive malignant peritoneal mesothelioma may be unique from those in pleural mesothelioma...
November 4, 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/27766425/reduced-expression-of-setd2-and-snx9-proteins-in-chemically-induced-mammary-tumorigenesis-in-wistar-rats-a-prognostic-histological-and-proteomic-study
#5
Ishfaq Ahmad Ganaie, Samar Husain Naqvi, Swatantra Kumar Jain, Saima Wajid
Breast cancer is a major global health concern, appealing for precise prognostic approaches. Thus, the need is to have studies focusing on the identification and recognition of preliminary events leading to the disease. The present study reports the tracing of precancerous progression and serum proteomic analysis in a breast cancer model developed as a result of 7,12-dimethylbenz[a]anthracene (DMBA) administration. Mammary gland histological changes of prime importance were examined by histopathology, and immunohistochemical analysis with Ki-67 was performed to monitor enhanced cell proliferation, right from the onset of hyperplasia till neoplasia...
October 20, 2016: Protoplasma
https://www.readbyqxmd.com/read/27764136/immunohistochemistry-successfully-uncovers-intratumoral-heterogeneity-and-widespread-co-losses-of-chromatin-regulators-in-clear-cell-renal-cell-carcinoma
#6
Wei Jiang, Essel Dulaimi, Karthik Devarajan, Theodore Parsons, Qiong Wang, Lili Liao, Eun-Ah Cho, Raymond O'Neill, Charalambos Solomides, Stephen C Peiper, Joseph R Testa, Robert Uzzo, Haifeng Yang
Recent studies have shown that intratumoral heterogeneity (ITH) is prevalent in clear cell renal cell carcinoma (ccRCC), based on DNA sequencing and chromosome aberration analysis of multiple regions from the same tumor. VHL mutations were found to be universal throughout individual tumors when it occurred (ubiquitous), while the mutations in other tumor suppressor genes tended to be detected only in parts of the tumors (subclonal). ITH has been studied mostly by DNA sequencing in limited numbers of samples, either by whole genome sequencing or by targeted sequencing...
2016: PloS One
https://www.readbyqxmd.com/read/27751729/genomic-biomarkers-of-a-randomized-trial-comparing-first-line-everolimus-and-sunitinib-in-patients-with-metastatic-renal-cell-carcinoma
#7
James J Hsieh, David Chen, Patricia I Wang, Mahtab Marker, Almedina Redzematovic, Ying-Bei Chen, S Duygu Selcuklu, Nils Weinhold, Nancy Bouvier, Kety H Huberman, Umesh Bhanot, Michael S Chevinsky, Parul Patel, Patrizia Pinciroli, Helen H Won, Daoqi You, Agnes Viale, William Lee, A Ari Hakimi, Michael F Berger, Nicholas D Socci, Emily H Cheng, Jennifer Knox, Martin H Voss, Maurizio Voi, Robert J Motzer
BACKGROUND: Metastatic renal cell carcinoma (RCC) patients are commonly treated with vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin inhibitors. Correlations between somatic mutations and first-line targeted therapy outcomes have not been reported on a randomized trial. OBJECTIVE: To evaluate the relationship between tumor mutations and treatment outcomes in RECORD-3, a randomized trial comparing first-line everolimus (mTOR inhibitor) followed by sunitinib (VEGF inhibitor) at progression with the opposite sequence in 471 metastatic RCC patients...
October 14, 2016: European Urology
https://www.readbyqxmd.com/read/27713405/molecular-analysis-of-aggressive-renal-cell-carcinoma-with-unclassified-histology-reveals-distinct-subsets
#8
Ying-Bei Chen, Jianing Xu, Anders Jacobsen Skanderup, Yiyu Dong, A Rose Brannon, Lu Wang, Helen H Won, Patricia I Wang, Gouri J Nanjangud, Achim A Jungbluth, Wei Li, Virginia Ojeda, A Ari Hakimi, Martin H Voss, Nikolaus Schultz, Robert J Motzer, Paul Russo, Emily H Cheng, Filippo G Giancotti, William Lee, Michael F Berger, Satish K Tickoo, Victor E Reuter, James J Hsieh
Renal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell renal cell carcinomas that have no standard therapy. The oncogenic drivers in these tumours are unknown. Here we perform a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, single-nucleotide polymorphism array, fluorescence in situ hybridization, immunohistochemistry and cell-based assays. We identify recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%) and MTOR (8%)...
October 7, 2016: Nature Communications
https://www.readbyqxmd.com/read/27687306/whole-exome-sequencing-and-immune-profiling-of-early-stage-lung-adenocarcinoma-with-fully-annotated-clinical-follow-up
#9
H Kadara, M Choi, J Zhang, E P Cuentas, J R Canales, S G Gaffney, Z Zhao, C Behrens, J Fujimoto, C Chow, Y Yoo, N Kalhor, C Moran, D Rimm, S Swisher, D L Gibbons, J Heymach, E Kaftan, J P Townsend, T J Lynch, J Schlessinger, J Lee, R P Lifton, I I Wistuba, R S Herbst
BACKGROUND: Lung adenocarcinomas (LUADs) lead to the majority of deaths attributable to lung cancer. We performed whole-exome sequencing (WES) and immune profiling analyses of a unique set of clinically annotated early-stage LUADs to better understand the pathogenesis of this disease and identify clinically relevant molecular markers. METHODS: We performed WES of 108 paired stage I-III LUADs and normal lung tissues using the Illumina HiSeq 2000 platform. Ten immune markers (PD-L1, PD-1, CD3, CD4, CD8, CD45ro, CD57, CD68, FOXP3 and Granzyme B) were profiled by imaging-based immunohistochemistry in a subset of LUADs (n=92)...
September 29, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27664394/improvement-in-survival-end-points-of-patients-with-metastatic-renal-cell-carcinoma-through-sequential-targeted-therapy
#10
Emiliano Calvo, Manuela Schmidinger, Daniel Y C Heng, Viktor Grünwald, Bernard Escudier
Survival of patients with metastatic renal cell carcinoma (mRCC) has improved since the advent of targeted therapy. Approved agents include the multi-targeted tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib, axitinib, pazopanib, cabozantinib, and lenvatinib (approved in combination with everolimus), the anti-VEGF monoclonal antibody bevacizumab, the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus, and the programmed death-1 (PD-1) targeted immune checkpoint inhibitor nivolumab...
September 10, 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/27614073/spop-containing-complex-regulates-setd2-stability-and-h3k36me3-coupled-alternative-splicing
#11
Kun Zhu, Pin-Ji Lei, Lin-Gao Ju, Xiang Wang, Kai Huang, Bo Yang, Changwei Shao, Yuan Zhu, Gang Wei, Xiang-Dong Fu, Lianyun Li, Min Wu
Trimethylation of histone H3K36 is a chromatin mark associated with active gene expression, which has been implicated in coupling transcription with mRNA splicing and DNA damage response. SETD2 is a major H3K36 trimethyltransferase, which has been implicated as a tumor suppressor in mammals. Here, we report the regulation of SETD2 protein stability by the proteasome system, and the identification of SPOP, a key subunit of the CUL3 ubiquitin E3 ligase complex, as a SETD2-interacting protein. We demonstrate that SPOP is critically involved in SETD2 stability control and that the SPOP/CUL3 complex is responsible for SETD2 polyubiquitination both in vivo and in vitro ChIP-Seq analysis and biochemical experiments demonstrate that modulation of SPOP expression confers differential H3K36me3 on SETD2 target genes, and induce H3K36me3-coupled alternative splicing events...
September 9, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27600764/type-ii-enteropathy-associated-t-cell-lymphoma-features-a-unique-genomic-profile-with-highly-recurrent-setd2-alterations
#12
Annalisa Roberti, Maria Pamela Dobay, Bettina Bisig, David Vallois, Cloé Boéchat, Evripidis Lanitis, Brigitte Bouchindhomme, Marie-Cécile Parrens, Céline Bossard, Leticia Quintanilla-Martinez, Edoardo Missiaglia, Philippe Gaulard, Laurence de Leval
Enteropathy-associated T-cell lymphoma (EATL), a rare and aggressive intestinal malignancy of intraepithelial T lymphocytes, comprises two disease variants (EATL-I and EATL-II) differing in clinical characteristics and pathological features. Here we report findings derived from whole-exome sequencing of 15 EATL-II tumour-normal tissue pairs. The tumour suppressor gene SETD2 encoding a non-redundant H3K36-specific trimethyltransferase is altered in 14/15 cases (93%), mainly by loss-of-function mutations and/or loss of the corresponding locus (3p21...
2016: Nature Communications
https://www.readbyqxmd.com/read/27594515/methylated-%C3%AE-tubulin-antibodies-recognize-a-new-microtubule-modification-on-mitotic-microtubules
#13
In Young Park, Pratim Chowdhury, Durga Nand Tripathi, Reid T Powell, Ruhee Dere, Esteban A Terzo, W Kimryn Rathmell, Cheryl Lyn Walker
Posttranslational modifications (PTMs) on microtubules differentiate these cytoskeletal elements for a variety of cellular functions. We recently identified SETD2 as a dual-function histone and microtubule methyltransferase, and methylation as a new microtubule PTM that occurs on lysine 40 of α-tubulin, which is trimethylated (α-TubK40me3) by SETD2. In the course of these studies, we generated polyclonal (α-TubK40me3 pAb) and monoclonal (α-TubK40me3 mAb) antibodies to a methylated α-tubulin peptide (GQMPSD-Kme3-TIGGGDC)...
September 3, 2016: MAbs
https://www.readbyqxmd.com/read/27571355/structure-of-the-epigenetic-oncogene-mmset-and-inhibition-by-n-alkyl-sinefungin-derivatives
#14
Dominic Tisi, Elisabetta Chiarparin, Emiliano Tamanini, Puja Pathuri, Joseph E Coyle, Adam Hold, Finn P Holding, Nader Amin, Agnes C L Martin, Sharna J Rich, Valerio Berdini, Jeff Yon, Paul Acklam, Rosemary Burke, Ludovic Drouin, Jenny E Harmer, Fiona Jeganathan, Rob L M van Montfort, Yvette Newbatt, Marcello Tortorici, Maura Westlake, Amy Wood, Swen Hoelder, Tom D Heightman
The members of the NSD subfamily of lysine methyl transferases are compelling oncology targets due to the recent characterization of gain-of-function mutations and translocations in several hematological cancers. To date, these proteins have proven intractable to small molecule inhibition. Here, we present initial efforts to identify inhibitors of MMSET (aka NSD2 or WHSC1) using solution phase and crystal structural methods. On the basis of 2D NMR experiments comparing NSD1 and MMSET structural mobility, we designed an MMSET construct with five point mutations in the N-terminal helix of its SET domain for crystallization experiments and elucidated the structure of the mutant MMSET SET domain at 2...
September 27, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27556922/an-integrative-genomics-approach-for-identifying-novel-functional-consequences-of-pbrm1-truncated-mutations-in-clear-cell-renal-cell-carcinoma-ccrcc
#15
Yuanyuan Wang, Xingyi Guo, Michael J Bray, Zhiyong Ding, Zhongming Zhao
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Recent large-scale next-generation sequencing analyses reveal that PBRM1 is the second most frequently mutated gene harboring many truncated mutations and has a suspected tumor suppressor role in ccRCC. However, the biological consequences of PBRM1 somatic mutations (e.g., truncated mutations) that drive tumor progression in ccRCC remain unclear. METHODS: In this study, we proposed an integrative genomics approach to explore the functional consequences of PBRM1 truncated mutations in ccRCC by incorporating somatic mutations, mRNA expression, DNA methylation, and microRNA (miRNA) expression profiles from The Cancer Genome Atlas (TCGA)...
August 22, 2016: BMC Genomics
https://www.readbyqxmd.com/read/27543584/setd2-mediated-microtubule-methylation-prevents-genomic-instability
#16
(no author information available yet)
SETD2 methylates α-tubulin to mediate cytoskeletal remodeling and maintain genomic stability.
October 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27528705/a-new-chromatin-cytoskeleton-link-in-cancer
#17
Amato J Giaccia
The set domain containing 2 (SETD2) histone methyltransferase, located at 3p2, specifically trimethylates lysine 36 of histone H3 (H3K36me3). H3K36me3 is an active mark involved in transcriptional elongation and RNA processing and a key regulator of DNA repair. In fact, SETD2 is the only methyltransferase that "writes" the H3K36me3 mark. Recent results from Park and colleagues have found a new role for SETD2 in the methylation of K40 of α-tubulin. Loss of SETD2 abolishes methylation of K40 of α-tubulin and results in a dysfunctional mitotic spindle and abnormalities in cytokinesis...
December 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/27528607/structure-function-analysis-of-recurrent-mutations-in-setd2-protein-reveals-a-critical-and-conserved-role-for-a-set-domain-residue-in-maintaining-protein-stability-and-histone-h3-lys-36-trimethylation
#18
Kathryn E Hacker, Catherine C Fahey, Stephen A Shinsky, Yun-Chen J Chiang, Julia V DiFiore, Deepak Kumar Jha, Andy H Vo, Jordan A Shavit, Ian J Davis, Brian D Strahl, W Kimryn Rathmell
The yeast Set2 histone methyltransferase is a critical enzyme that plays a number of key roles in gene transcription and DNA repair. Recently, the human homologue, SETD2, was found to be recurrently mutated in a significant percentage of renal cell carcinomas, raising the possibility that the activity of SETD2 is tumor-suppressive. Using budding yeast and human cell line model systems, we examined the functional significance of two evolutionarily conserved residues in SETD2 that are recurrently mutated in human cancers...
September 30, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27518565/dual-chromatin-and-cytoskeletal-remodeling-by-setd2
#19
In Young Park, Reid T Powell, Durga Nand Tripathi, Ruhee Dere, Thai H Ho, T Lynne Blasius, Yun-Chen Chiang, Ian J Davis, Catherine C Fahey, Kathryn E Hacker, Kristen J Verhey, Mark T Bedford, Eric Jonasch, W Kimryn Rathmell, Cheryl Lyn Walker
Posttranslational modifications (PTMs) of tubulin specify microtubules for specialized cellular functions and comprise what is termed a "tubulin code." PTMs of histones comprise an analogous "histone code," although the "readers, writers, and erasers" of the cytoskeleton and epigenome have heretofore been distinct. We show that methylation is a PTM of dynamic microtubules and that the histone methyltransferase SET-domain-containing 2 (SETD2), which is responsible for H3 lysine 36 trimethylation (H3K36me3) of histones, also methylates α-tubulin at lysine 40, the same lysine that is marked by acetylation on microtubules...
August 11, 2016: Cell
https://www.readbyqxmd.com/read/27474439/molecular-basis-for-oncohistone-h3-recognition-by-setd2-methyltransferase
#20
Shuang Yang, Xiangdong Zheng, Chao Lu, Guo-Min Li, C David Allis, Haitao Li
High-frequency point mutations of genes encoding histones have been identified recently as novel drivers in a number of tumors. Specifically, the H3K36M/I mutations were shown to be oncogenic in chondroblastomas and undifferentiated sarcomas by inhibiting H3K36 methyltransferases, including SETD2. Here we report the crystal structures of the SETD2 catalytic domain bound to H3K36M or H3K36I peptides with SAH (S-adenosylhomocysteine). In the complex structure, the catalytic domain adopts an open conformation, with the K36M/I peptide snuggly positioned in a newly formed substrate channel...
July 15, 2016: Genes & Development
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