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Cancer AND CRISPR-Cas9

Ali Zarei, Vahid Razban, Seyed Ebrahim Hosseini, Seyed Mohammad Bagher Tabei
AIMS: Set of unique sequences in bacterial genomes, responsible for protecting bacteria against bacteriophages, have been recently used for genetic manipulation of specific points in the genome. These system comprises of one RNA component and one enzyme component, known as CRISPR and Cas9, respectively. The present review focuses on the applications of the CRISPR/Cas9 technology in the development of cellular and animal models of human disease. DISCUSSION: Making a desired genetic alteration depend on the design of RNA molecules that guide endonucleases to a favorable genomic location...
February 20, 2019: Journal of Gene Medicine
Bethany N Hannafon, Amy L Gin, Yi-Fan Xu, Matthew Bruns, Cameron L Calloway, Wei-Qun Ding
BACKGROUND: Exosomes are small membrane-bound vesicles that contribute to tumor progression and metastasis by mediating cell-to-cell communication and modifying the tumor microenvironment at both local and distant sites. However, little is known about the predominant factors in exosomes that contribute to breast cancer (BC) progression. MTA1 is a transcriptional co-regulator that can act as both a co-activator and co-repressor to regulate pathways that contribute to cancer development...
February 19, 2019: Cell Communication and Signaling: CCS
Dionysia Dimitrakopoulou, Dieter Tulkens, Pieter Van Vlieberghe, Kris Vleminckx
Aquatic vertebrate organisms such as zebrafish have been used for over a decade to model different types of human cancer, including hematologic malignancies. However, the introduction of gene editing techniques such as CRISPR/Cas9 and TALEN, have now opened the road for other organisms featuring large externally developing embryos that are easily accessible. Thanks to its unique diploid genome that shows a high degree of synteny to the human, combined with its relatively short live cycle, Xenopus tropicalis has now emerged as an additional powerful aquatic model for studying human disease genes...
2019: Frontiers in Physiology
Kevin Dzobo
The human epigenome plays a key role in determining cellular identity and eventually function. Drug discovery undertakings have focused mainly on the role of genomics in carcinogenesis, with the focus turning to the epigenome recently. Drugs targeting DNA and histone modifications are under development with some such as 5-azacytidine, decitabine, vorinostat, and panobinostat already approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This expert review offers a critical analysis of the epigenomics-guided drug discovery and development and the opportunities and challenges for the next decade...
February 2019: Omics: a Journal of Integrative Biology
Timothy A Dinh, Mark L Jewell, Matt Kanke, Adam Francisco, Ramja Sritharan, Rigney E Turnham, Seona Lee, Edward R Kastenhuber, Eliane Wauthier, Cynthia D Guy, Raymond S Yeung, Scott W Lowe, Lola M Reid, John D Scott, Anna M Diehl, Praveen Sethupathy
BACKGROUND & AIMS: Fibrolamellar carcinoma is a rare liver cancer that primarily affects adolescents and young adults. It is characterized by a heterozygous ∼400 kb deletion on chromosome 19 that results in a unique DNAJB1-PRKACA fusion. The role of microRNAs (miRNAs) in FLC remains unclear. We identified dysregulated miRNAs in FLC and investigated whether dysregulation of one key miRNA contributes to FLC pathogenesis. METHODS: We analyzed small RNA sequencing (smRNA-seq) data from The Cancer Genome Atlas (TCGA) to identified dysregulated miRNAs in primary FLC tumors and validated the findings in three independent FLC cohorts...
February 11, 2019: Cellular and Molecular Gastroenterology and Hepatology
Yucheng Guo, Chen Bao, Dacheng Ma, Yubing Cao, Yanda Li, Zhen Xie, Shao Li
Tumorigenesis is a complex process that is driven by a combination of the networks of genes and environmental factors; however, efficient approaches for identifying functional networks that are perturbed by the process of tumorigenesis is poorly understood. Then, the identification of functional synergistic modules and pathways is often limited by computational method and experiment measures. Here, we propose an integrated network-based approach for the systematic discovery of functional synergistic modules that are causal determinants of inflammation-induced tumorigenesis, by prioritizing candidate genes of integrating clinical-based and network-based genome-wide gene prediction methods and identify functional synergistic modules based on combinatorial CRISPR-Cas9 screens...
February 14, 2019: ACS Synthetic Biology
Stevephen Hung, Alina Saiakhova, Zachary J Faber, Cynthia F Bartels, Devin Neu, Ian Bayles, Evelyn Ojo, Ellen S Hong, W Dean Pontius, Andrew R Morton, Ruifu Liu, Matthew F Kalady, David N Wald, Sanford Markowitz, Peter C Scacheri
Commonly-mutated genes have been found for many cancers, but less is known about mutations in cis-regulatory elements. We leverage gains in tumor-specific enhancer activity, coupled with allele-biased mutation detection from H3K27ac ChIP-seq data, to pinpoint potential enhancer-activating mutations in colorectal cancer (CRC). Analysis of a genetically-diverse cohort of CRC specimens revealed that microsatellite instable (MSI) samples have a high indel rate within active enhancers. Enhancers with indels show evidence of positive selection, increased target gene expression, and a subset is highly recurrent...
February 13, 2019: ELife
Thomas P Howard, Taylor E Arnoff, Melinda R Song, Andrew O Giacomelli, Xiaofeng Wang, Andrew L Hong, Neekesh V Dharia, Su Wang, Francisca Vazquez, Minh-Tam Pham, Ann M Morgan, Franziska Wachter, Gregory H Bird, Guillaume Kugener, Elaine M Oberlick, Matthew G Rees, Hong L Tiv, Justin H Hwang, Katherine H Walsh, April Cook, John M Krill-Burger, Aviad Tsherniak, Prafulla C Gokhale, Peter J Park, Kimberly Stegmaier, Loren D Walensky, William C Hahn, Charles W M Roberts
Malignant rhabdoid tumors (MRT) are highly aggressive pediatric cancers that respond poorly to current therapies. In this study, we screened several MRT cell lines with large-scale RNAi, CRISPR-Cas9, and small-molecule libraries to identify potential drug targets specific for these cancers. We discovered MDM2 and MDM4, the canonical negative regulators of p53, as significant vulnerabilities. Using two compounds currently in clinical development, idasanutlin (MDM2-specific) and ATSP-7041 (MDM2/4-dual), we show that MRT cells were more sensitive than other p53 wild-type cancer cell lines to inhibition of MDM2 alone as well as dual inhibition of MDM2/4...
February 12, 2019: Cancer Research
Fabrizio Alberti, Daniel J Leng, Ina Wilkening, Lijiang Song, Manuela Tosin, Christophe Corre
In this study, we report the rapid characterisation of a novel microbial natural product resulting from the rational derepression of a silent gene cluster. A conserved set of five regulatory genes was used as a query to search genomic databases and identify atypical biosynthetic gene clusters (BGCs). A 20-kb BGC from the genetically intractable Streptomyces sclerotialus bacterial strain was captured using yeast-based homologous recombination and introduced into validated heterologous hosts. CRISPR/Cas9-mediated genome editing was then employed to rationally inactivate the key transcriptional repressor and trigger production of an unprecedented class of hybrid natural products exemplified by (2-(benzoyloxy)acetyl)-l-proline, named scleric acid...
January 14, 2019: Chemical Science
Wenjing Gong, Youde Liu, Huajun Qu, Aina Liu, Ping Sun, Xiumei Wang
Chromatin spatial organization is essential for transcriptional modulation and stabilization. The pattern of DNA distal interplay form the multiple topological associating domains (TADs), and further assemble the functional compartmentalization with open and expression-active chromatin ("A" compartments) or closed and expression-inactive chromatin ("B" compartments) in genome, whose boundaries were defined by the high enrichment of CCCTC-binding factor (CTCF). Nevertheless, As a potential therapeutic strategy, changing the local chromatin architecture via adding or removing the CTCF binding sites in situ to regulate the transcription activity of genes within one TAD in cancer cells is poorly explored...
February 6, 2019: Biochemical and Biophysical Research Communications
Bo Zhou, Steve S Ho, Stephanie U Greer, Xiaowei Zhu, John M Bell, Joseph G Arthur, Noah Spies, Xianglong Zhang, Seunggyu Byeon, Reenal Pattni, Noa Ben-Efraim, Michael S Haney, Rajini R Haraksingh, Giltae Song, Hanlee P Ji, Dimitri Perrin, Wing H Wong, Alexej Abyzov, Alexander E Urban
K562 is widely used in biomedical research. It is one of three tier-one cell lines of ENCODE and also most commonly used for large-scale CRISPR/Cas9 screens. Although its functional genomic and epigenomic characteristics have been extensively studied, its genome sequence and genomic structural features have never been comprehensively analyzed. Such information is essential for the correct interpretation and understanding of the vast troves of existing functional genomics and epigenomics data for K562. We performed and integrated deep-coverage whole-genome (short-insert), mate-pair, and linked-read sequencing as well as karyotyping and array CGH analysis to identify a wide spectrum of genome characteristics in K562: copy numbers (CN) of aneuploid chromosome segments at high-resolution, SNVs and indels (both corrected for CN in aneuploid regions), loss of heterozygosity, megabase-scale phased haplotypes often spanning entire chromosome arms, structural variants (SVs), including small and large-scale complex SVs and nonreference retrotransposon insertions...
February 8, 2019: Genome Research
January Salas-Mckee, Weimin Kong, Whitney L Gladney, Julie K Jadlowsky, Gabriela Plesa, Megan M Davis, Joseph A Fraietta
The advent of engineered T cells as a form of immunotherapy marks the beginning of a new era in medicine, providing a transformative way to combat complex diseases such as cancer. Following FDA approval of CAR T cells directed against the CD19 protein for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma, CAR T cells are poised to enter mainstream oncology. Despite this success, a number of patients are unable to receive this therapy due to inadequate T cell numbers or rapid disease progression...
February 8, 2019: Human Vaccines & Immunotherapeutics
Yuki Yoshino, Shino Endo, Zhenghao Chen, Huicheng Qi, Gou Watanabe, Natsuko Chiba
Homologous recombination (HR) contributes to the repair of DNA double-strand breaks (DSBs) and inter-strand crosslinks. The HR activity in cancer cells can be used to predict their sensitivity to DNA-damaging agents that cause these damages. To evaluate HR activity, we developed a system called Assay for Site-specific HR Activity (ASHRA), in which cells are transiently transfected with an expression vector for CRISPR/Cas9 and a HR donor sequence containing a marker gene. DSBs are created by Cas9 and then repaired by HR using donor vector sequences homologous to the target gene...
February 7, 2019: Scientific Reports
Roslyn Tedja, Cai M Roberts, Ayesha B Alvero, Carlos Cardenas, Yang Yang-Hartwich, Sydney Spadinger, Mary Pitruzzello, Gang Yin, Carlotta A Glackin, Gil Mor
Twist1 is a basic helix-loop-helix transcription factor that plays a key role in embryonic development, and its expression is down-regulated in adult cells. However, Twist1 is highly expressed during cancer development, conferring a proliferative, migratory, and invasive phenotype to malignant cells. Twist1 expression can be regulated post-translationally by phosphorylation or ubiquitination events. We report in this study a previously unknown and relevant Twist1 phosphorylation site that controls its stability...
February 7, 2019: Journal of Biological Chemistry
Felice Ho-Ching Tsang, Cheuk-Ting Law, Chloe Tsz-Ching Tang, Carol Lai-Hung Cheng, Don Wai-Ching Chin, Vincy Wing-Sum Tam, Lai Wei, Carmen Chak-Lui Wong, Irene Oi-Lin Ng, Chun-Ming Wong
Hepatocellular carcinoma (HCC) cells exploit an aberrant transcriptional program to sustain their infinite growth and progression. Emerging evidence indicates that the continuous and robust transcription of oncogenes in cancer cells is often driven by super-enhancers (SEs). In this study, we systematically compared the SE-landscapes between normal liver and HCC cells and revealed that the cis-acting SE-landscape was extensively reprogrammed during liver carcinogenesis. HCC cells acquired SEs at multiple prominent oncogenes to drive their vigorous expression...
February 5, 2019: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Emanuel Gonçalves, Fiona M Behan, Sandra Louzada, Damien Arnol, Euan A Stronach, Fengtang Yang, Kosuke Yusa, Oliver Stegle, Francesco Iorio, Mathew J Garnett
BACKGROUND: CRISPR-Cas9 genome editing is widely used to study gene function, from basic biology to biomedical research. Structural rearrangements are a ubiquitous feature of cancer cells and their impact on the functional consequences of CRISPR-Cas9 gene-editing has not yet been assessed. RESULTS: Utilizing CRISPR-Cas9 knockout screens for 250 cancer cell lines, we demonstrate that targeting structurally rearranged regions, in particular tandem or interspersed amplifications, is highly detrimental to cellular fitness in a gene-independent manner...
February 5, 2019: Genome Biology
Hexiao Shen, Li Li, Zhaowei Teng, Tianqing Meng, Xiangbin Kong, Yan Hu, Yun Zhu, Lixin Ma
MicroRNAs (miRNAs) bind to the 3'-untranslated region of target mRNAs in a sequence-specific manner and subsequently repress gene translation. Human miR-26a has been studied extensively, but the target transcripts are far from complete. We first employed the CRISPR-Cas9 system to generate an miR-26a-knockout line in human cervical cancer HeLa cells. The miR26a-knockout line showed increased cell growth and altered proliferation. Proteomics technology of sequential window acquisition of all theoretical mass spectra (SWATH-MS) was utilized to compare the protein abundance between the wild-type and the knockout lines, with an attempt to identify transcripts whose translation was influenced by miR-26a...
February 4, 2019: Scientific Reports
Serge Hardy, Elie Kostantin, Shan Jin Wang, Tzvetena Hristova, Gabriela Galicia-Vázquez, Pavel V Baranov, Jerry Pelletier, Michel L Tremblay
Phosphatases of regenerating liver (PRL-1, PRL-2, and PRL-3, also known as PTP4A1, PTP4A2, and PTP4A3) control magnesium homeostasis through an association with the CNNM magnesium transport regulators. Although high PRL levels have been linked to cancer progression, regulation of their expression is poorly understood. Here we show that modulating intracellular magnesium levels correlates with a rapid change of PRL expression by a mechanism involving its 5'UTR mRNA region. Mutations or CRISPR-Cas9 targeting of the conserved upstream ORF present in the mRNA leader derepress PRL protein synthesis and attenuate the translational response to magnesium levels...
February 4, 2019: Proceedings of the National Academy of Sciences of the United States of America
Ruibo Wang, Yantong Liu, Li Liu, Mei Chen, Xiuxuan Wang, Jingyun Yang, Yanqiu Gong, Bi-Sen Ding, Yuquan Wei, Xiawei Wei
BACKGROUND: Tumor cells benefit from tumor-associated macrophages (TAMs) promoting tumor growth and modulating functions of other cells in tumor microenvironment (TME). However, how tumor cells regulate the property of TAMs during tumor invasion remains to be defined. METHODS: Mouse tumor models and cancer patients' samples were analyzed to determine LAMP2a expression in TAMs. In vitro mouse primary macrophages were used to assess LAMP2a-modulated macrophage activation, and to verify LAMP2a's target proteins...
January 30, 2019: EBioMedicine
Steven E Kirberger, Peter D Ycas, Jorden A Johnson, Chen Chen, Michael F Ciccone, Rinette W L Woo, Andrew K Urick, Huda Zahid, Ke Shi, Hideki Aihara, Sean D McAllister, Mohammed Kashani-Sabet, Junwei Shi, Alex Dickson, Camila O Dos Santos, William C K Pomerantz
Bromodomain and PHD finger containing protein transcription factor (BPTF) is an epigenetic protein involved in chromatin remodelling and is a potential anticancer target. The BPTF bromodomain has one reported small molecule inhibitor (AU1, rac-1). Here, advances made on the structure-activity relationship of a BPTF bromodomain ligand are reported using a combination of experimental and molecular dynamics simulations leading to the active enatiomer (S)-1. Additionally, a ligand deconstruction analysis was conducted to characterize important pharmacophores for engaging the BPTF bromodomain...
February 1, 2019: Organic & Biomolecular Chemistry
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