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Christopher R. Vakoc

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https://www.readbyqxmd.com/read/27590350/multi-focal-control-of-mitochondrial-gene-expression-by-oncogenic-myc-provides-potential-therapeutic-targets-in-cancer
#1
Amanda R Oran, Clare M Adams, Xiao-Yong Zhang, Victoria J Gennaro, Harla K Pfeiffer, Hestia S Mellert, Hans E Seidel, Kirsten Mascioli, Jordan Kaplan, Mahmoud R Gaballa, Chen Shen, Isidore Rigoutsos, Michael P King, Justin L Cotney, Jamie J Arnold, Suresh D Sharma, Ubaldo E Martinez-Outschoorn, Christopher R Vakoc, Lewis A Chodosh, James E Thompson, James E Bradner, Craig E Cameron, Gerald S Shadel, Christine M Eischen, Steven B McMahon
Despite ubiquitous activation in human cancer, essential downstream effector pathways of the MYC transcription factor have been difficult to define and target. Using a structure/function-based approach, we identified the mitochondrial RNA polymerase (POLRMT) locus as a critical downstream target of MYC. The multifunctional POLRMT enzyme controls mitochondrial gene expression, a process required both for mitochondrial function and mitochondrial biogenesis. We further demonstrate that inhibition of this newly defined MYC effector pathway causes robust and selective tumor cell apoptosis, via an acute, checkpoint-like mechanism linked to aberrant electron transport chain complex assembly and mitochondrial reactive oxygen species (ROS) production...
August 31, 2016: Oncotarget
https://www.readbyqxmd.com/read/27471963/a-biomarker-harvest-from-one-thousand-cancer-cell-lines
#2
COMMENT
Yu-Han Huang, Christopher R Vakoc
Identifying molecular biomarkers that predict cancer drug efficacy is crucial for the advancement of precision medicine. In this issue of Cell, Iorio et al. nominate hundreds of potential genetic and epigenetic biomarkers through high-throughput drug screening in ∼1,000 molecularly annotated cancer cell lines.
July 28, 2016: Cell
https://www.readbyqxmd.com/read/27411582/modeling-the-epigenetic-chain-reaction-downstream-of-dnmt3a-r882h
#3
Tim D D Somerville, Christopher R Vakoc
In this issue of Cancer Cell, Lu et al. use a mouse model of DNMT3A(R882H)/NRAS(G12D) acute myeloid leukemia to define a cascade of chromatin changes that emanate from DNMT3A-bound enhancers to initiate disease. The authors also reveal a chemical strategy to interrupt this process.
July 11, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27376689/sensitivity-and-engineered-resistance-of-myeloid-leukemia-cells-to-brd9-inhibition
#4
Anja F Hohmann, Laetitia J Martin, Jessica L Minder, Jae-Seok Roe, Junwei Shi, Steffen Steurer, Gerd Bader, Darryl McConnell, Mark Pearson, Thomas Gerstberger, Teresa Gottschamel, Diane Thompson, Yutaka Suzuki, Manfred Koegl, Christopher R Vakoc
Here we show that acute myeloid leukemia (AML) cells require the BRD9 subunit of the SWI-SNF chromatin-remodeling complex to sustain MYC transcription, rapid cell proliferation and a block in differentiation. Based on these observations, we derived small-molecule inhibitors of the BRD9 bromodomain that selectively suppress the proliferation of mouse and human AML cell lines. To establish these effects as on-target, we engineered a bromodomain-swap allele of BRD9 that retains functionality despite a radically altered bromodomain pocket...
September 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27291650/structural-mechanism-of-transcriptional-regulator-nsd3-recognition-by-the-et-domain-of-brd4
#5
Qiang Zhang, Lei Zeng, Chen Shen, Ying Ju, Tsuyoshi Konuma, Chengcheng Zhao, Christopher R Vakoc, Ming-Ming Zhou
The bromodomains and extra-terminal domain (BET) proteins direct gene transcription in chromatin, and represent new drug targets for cancer and inflammation. Here we report that the ET domain of the BET protein BRD4 recognizes an amphipathic protein sequence motif through establishing a two-strand antiparallel β sheet anchored on a hydrophobic cleft of the three-helix bundle. This structural mechanism likely explains BRD4 interactions with numerous cellular and viral proteins such as Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen, and NSD3 whose interaction with BRD4 via this ET domain mechanism is essential for acute myeloid leukemia maintenance...
July 6, 2016: Structure
https://www.readbyqxmd.com/read/27099234/brd4-connects-enhancer-remodeling-to-senescence-immune-surveillance
#6
Nilgun Tasdemir, Ana Banito, Jae-Seok Roe, Direna Alonso-Curbelo, Matthew Camiolo, Darjus F Tschaharganeh, Chun-Hao Huang, Ozlem Aksoy, Jessica E Bolden, Chi-Chao Chen, Myles Fennell, Vishal Thapar, Agustin Chicas, Christopher R Vakoc, Scott W Lowe
UNLABELLED: Oncogene-induced senescence is a potent barrier to tumorigenesis that limits cellular expansion following certain oncogenic events. Senescent cells display a repressive chromatin configuration thought to stably silence proliferation-promoting genes while simultaneously activating an unusual form of immune surveillance involving a secretory program referred to as the senescence-associated secretory phenotype (SASP). Here, we demonstrate that senescence also involves a global remodeling of the enhancer landscape with recruitment of the chromatin reader BRD4 to newly activated super-enhancers adjacent to key SASP genes...
June 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27068464/bet-bromodomain-inhibition-releases-the-mediator-complex-from-select-cis-regulatory-elements
#7
Anand S Bhagwat, Jae-Seok Roe, Beverly Y L Mok, Anja F Hohmann, Junwei Shi, Christopher R Vakoc
The bromodomain and extraterminal (BET) protein BRD4 can physically interact with the Mediator complex, but the relevance of this association to the therapeutic effects of BET inhibitors in cancer is unclear. Here, we show that BET inhibition causes a rapid release of Mediator from a subset of cis-regulatory elements in the genome of acute myeloid leukemia (AML) cells. These sites of Mediator eviction were highly correlated with transcriptional suppression of neighboring genes, which are enriched for targets of the transcription factor MYB and for functions related to leukemogenesis...
April 19, 2016: Cell Reports
https://www.readbyqxmd.com/read/26914985/structure-based-design-of-an-in-vivo-active-selective-brd9-inhibitor
#8
Laetitia J Martin, Manfred Koegl, Gerd Bader, Xiao-Ling Cockcroft, Oleg Fedorov, Dennis Fiegen, Thomas Gerstberger, Marco H Hofmann, Anja F Hohmann, Dirk Kessler, Stefan Knapp, Petr Knesl, Stefan Kornigg, Susanne Müller, Herbert Nar, Catherine Rogers, Klaus Rumpel, Otmar Schaaf, Steffen Steurer, Cynthia Tallant, Christopher R Vakoc, Markus Zeeb, Andreas Zoephel, Mark Pearson, Guido Boehmelt, Darryl McConnell
Components of the chromatin remodelling switch/sucrose nonfermentable (SWI/SNF) complex are recurrently mutated in tumors, suggesting that altering the activity of the complex plays a role in oncogenesis. However, the role that the individual subunits play in this process is not clear. We set out to develop an inhibitor compound targeting the bromodomain of BRD9 in order to evaluate its function within the SWI/SNF complex. Here, we present the discovery and development of a potent and selective BRD9 bromodomain inhibitor series based on a new pyridinone-like scaffold...
May 26, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/26645049/targeting-transcription-factors-in-cancer
#9
Anand S Bhagwat, Christopher R Vakoc
Transcription factors (TFs) are commonly deregulated in the pathogenesis of human cancer and are a major class of cancer cell dependencies. Consequently, targeting of TFs can be highly effective in treating particular malignancies, as highlighted by the clinical efficacy of agents that target nuclear hormone receptors. In this review we discuss recent advances in our understanding of TFs as drug targets in oncology, with an emphasis on the emerging chemical approaches to modulate TF function. The remarkable diversity and potency of TFs as drivers of cell transformation justifies a continued pursuit of TFs as therapeutic targets for drug discovery...
September 1, 2015: Trends in Cancer
https://www.readbyqxmd.com/read/26626481/nsd3-short-is-an-adaptor-protein-that-couples-brd4-to-the-chd8-chromatin-remodeler
#10
Chen Shen, Jonathan J Ipsaro, Junwei Shi, Joseph P Milazzo, Eric Wang, Jae-Seok Roe, Yutaka Suzuki, Darryl J Pappin, Leemor Joshua-Tor, Christopher R Vakoc
The bromodomain and extraterminal (BET) protein BRD4 is a therapeutic target in acute myeloid leukemia (AML). Here, we demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. We show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by using a PWWP chromatin reader module, and by employing an acidic transactivation domain...
December 17, 2015: Molecular Cell
https://www.readbyqxmd.com/read/26447190/functional-genetic-dissection-of-hdac-dependencies-in-mouse-lymphoid-and-myeloid-malignancies
#11
Geoffrey M Matthews, Parinaz Mehdipour, Leonie A Cluse, Katrina J Falkenberg, Eric Wang, Mareike Roth, Fabio Santoro, Eva Vidacs, Kym Stanley, Colin M House, James R Rusche, Christopher R Vakoc, Johannes Zuber, Saverio Minucci, Ricky W Johnstone
Histone deacetylase (HDAC) inhibitors (HDACis) have demonstrated activity in hematological and solid malignancies. Vorinostat, romidepsin, belinostat, and panobinostat are Food and Drug Administration-approved for hematological malignancies and inhibit class II and/or class I HDACs, including HDAC1, 2, 3, and 6. We combined genetic and pharmacological approaches to investigate whether suppression of individual or multiple Hdacs phenocopied broad-acting HDACis in 3 genetically distinct leukemias and lymphomas...
November 19, 2015: Blood
https://www.readbyqxmd.com/read/26367798/transcriptional-plasticity-promotes-primary-and-acquired-resistance-to-bet-inhibition
#12
Philipp Rathert, Mareike Roth, Tobias Neumann, Felix Muerdter, Jae-Seok Roe, Matthias Muhar, Sumit Deswal, Sabine Cerny-Reiterer, Barbara Peter, Julian Jude, Thomas Hoffmann, Łukasz M Boryń, Elin Axelsson, Norbert Schweifer, Ulrike Tontsch-Grunt, Lukas E Dow, Davide Gianni, Mark Pearson, Peter Valent, Alexander Stark, Norbert Kraut, Christopher R Vakoc, Johannes Zuber
Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukaemia (AML), bromodomain and extra terminal protein (BET) inhibitors are being explored as a promising therapeutic avenue in numerous cancers. While clinical trials have reported single-agent activity in advanced haematological malignancies, mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukaemia, here we perform a chromatin-focused RNAi screen in a sensitive MLL-AF9;Nras(G12D)-driven AML mouse model, and investigate dynamic transcriptional profiles in sensitive and resistant mouse and human leukaemias...
September 24, 2015: Nature
https://www.readbyqxmd.com/read/25982114/bet-bromodomain-inhibition-suppresses-the-function-of-hematopoietic-transcription-factors-in-acute-myeloid-leukemia
#13
Jae-Seok Roe, Fatih Mercan, Keith Rivera, Darryl J Pappin, Christopher R Vakoc
The bromodomain and extraterminal (BET) protein BRD4 is a validated drug target in leukemia, yet its regulatory function in this disease is not well understood. Here, we show that BRD4 chromatin occupancy in acute myeloid leukemia closely correlates with the hematopoietic transcription factors (TFs) PU.1, FLI1, ERG, C/EBPα, C/EBPβ, and MYB at nucleosome-depleted enhancer and promoter regions. We provide evidence that these TFs, in conjunction with the lysine acetyltransferase activity of p300/CBP, facilitate BRD4 recruitment to their occupied sites to promote transcriptional activation...
June 18, 2015: Molecular Cell
https://www.readbyqxmd.com/read/25961408/discovery-of-cancer-drug-targets-by-crispr-cas9-screening-of-protein-domains
#14
Junwei Shi, Eric Wang, Joseph P Milazzo, Zihua Wang, Justin B Kinney, Christopher R Vakoc
CRISPR-Cas9 genome editing technology holds great promise for discovering therapeutic targets in cancer and other diseases. Current screening strategies target CRISPR-Cas9-induced mutations to the 5' exons of candidate genes, but this approach often produces in-frame variants that retain functionality, which can obscure even strong genetic dependencies. Here we overcome this limitation by targeting CRISPR-Cas9 mutagenesis to exons encoding functional protein domains. This generates a higher proportion of null mutations and substantially increases the potency of negative selection...
June 2015: Nature Biotechnology
https://www.readbyqxmd.com/read/25919951/the-transcriptional-cofactor-trim33-prevents-apoptosis-in-b-lymphoblastic-leukemia-by-deactivating-a-single-enhancer
#15
Eric Wang, Shinpei Kawaoka, Jae-Seok Roe, Junwei Shi, Anja F Hohmann, Yali Xu, Anand S Bhagwat, Yutaka Suzuki, Justin B Kinney, Christopher R Vakoc
Most mammalian transcription factors (TFs) and cofactors occupy thousands of genomic sites and modulate the expression of large gene networks to implement their biological functions. In this study, we describe an exception to this paradigm. TRIM33 is identified here as a lineage dependency in B cell neoplasms and is shown to perform this essential function by associating with a single cis element. ChIP-seq analysis of TRIM33 in murine B cell leukemia revealed a preferential association with two lineage-specific enhancers that harbor an exceptional density of motifs recognized by the PU...
April 28, 2015: ELife
https://www.readbyqxmd.com/read/25644601/tgf-%C3%AE-smad-signaling-through-dock4-facilitates-lung-adenocarcinoma-metastasis
#16
Jia-Ray Yu, Yilin Tai, Ying Jin, Molly C Hammell, J Erby Wilkinson, Jae-Seok Roe, Christopher R Vakoc, Linda Van Aelst
The mechanisms by which TGF-β promotes lung adenocarcinoma (ADC) metastasis are largely unknown. Here, we report that in lung ADC cells, TGF-β potently induces expression of DOCK4, but not other DOCK family members, via the Smad pathway and that DOCK4 induction mediates TGF-β's prometastatic effects by enhancing tumor cell extravasation. TGF-β-induced DOCK4 stimulates lung ADC cell protrusion, motility, and invasion without affecting epithelial-to-mesenchymal transition. These processes, which are fundamental to tumor cell extravasation, are driven by DOCK4-mediated Rac1 activation, unveiling a novel link between TGF-β and Rac1...
February 1, 2015: Genes & Development
https://www.readbyqxmd.com/read/25402979/gain-of-function-mutation-of-chromatin-regulators-as-a-tumorigenic-mechanism-and-an-opportunity-for-therapeutic-intervention
#17
REVIEW
Chen Shen, Christopher R Vakoc
PURPOSE OF REVIEW: Somatic gain-of-function mutations that drive cancer pathogenesis are well established opportunities for therapeutic intervention, as demonstrated by the clinical efficacy of kinase inhibitors in kinase-mutant malignancies. Here, we discuss the recently discovered gain-of-function mutations in chromatin-regulatory machineries that promote the pathogenesis of cancer. The current understanding of the underlying molecular mechanisms and the therapeutic potential for direct chemical inhibition will be reviewed...
January 2015: Current Opinion in Oncology
https://www.readbyqxmd.com/read/25288306/brd4-is-on-the-move-during-inflammation
#18
COMMENT
Yali Xu, Christopher R Vakoc
Enhancer landscapes are shaped by the integrated functions of lineage-specific and signal-dependent transcription factors. A new study by Brown et al. suggests that the signal-dependent transcription factor NF-kB can modulate global enhancer activities by altering the occupancy of Brd4, a BET bromodomain coactivator protein, across the genome. This work reveals new principles of enhancer dynamics and insights into the therapeutic modulation of enhancer function with BET bromodomain inhibitors.
November 2014: Trends in Cell Biology
https://www.readbyqxmd.com/read/24932742/a-rationale-to-target-the-swi-snf-complex-for-cancer-therapy
#19
REVIEW
Anja F Hohmann, Christopher R Vakoc
SWI/SNF is a multisubunit chromatin-remodeling complex that performs fundamental roles in gene regulation, cell lineage specification, and organismal development. Mutations that inactivate SWI/SNF subunits are found in nearly 20% of human cancers, which indicates that the proper functioning of this complex is necessary to prevent tumor formation in diverse tissues. Recent studies show that SWI/SNF-mutant cancers depend on residual SWI/SNF complexes for their aberrant growth, thus revealing synthetic lethal interactions that could be exploited for therapeutic purposes...
August 2014: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/24910429/acquired-dependence-of-acute-myeloid-leukemia-on-the-dead-box-rna-helicase-ddx5
#20
Anthony Mazurek, Youngkyu Park, Cornelius Miething, John E Wilkinson, Jesse Gillis, Scott W Lowe, Christopher R Vakoc, Bruce Stillman
Acute myeloid leukemia (AML) therapy involves compounds that are cytotoxic to both normal and cancer cells, and relapsed AML is resistant to subsequent chemotherapy. Thus, agents are needed that selectively kill AML cells with minimal toxicity. Here, we report that AML is dependent on DDX5 and that inhibiting DDX5 expression slows AML cell proliferation in vitro and AML progression in vivo but is not toxic to cells from normal bone marrow. Inhibition of DDX5 expression in AML cells induces apoptosis via induction of reactive oxygen species (ROS)...
June 26, 2014: Cell Reports
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