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CRISPR AND epigenetic AND Cancer

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https://www.readbyqxmd.com/read/30537986/a-novel-fli1-exonic-circular-rna-promotes-metastasis-in-breast-cancer-by-coordinately-regulating-tet1-and-dnmt1
#1
Naifei Chen, Gang Zhao, Xu Yan, Zheng Lv, Hongmei Yin, Shilin Zhang, Wei Song, Xueli Li, Lingyu Li, Zhonghua Du, Lin Jia, Lei Zhou, Wei Li, Andrew R Hoffman, Ji-Fan Hu, Jiuwei Cui
BACKGROUND: Friend leukemia virus integration 1 (FLI1), an ETS transcription factor family member, acts as an oncogenic driver in hematological malignancies and promotes tumor growth in solid tumors. However, little is known about the mechanisms underlying the activation of this proto-oncogene in tumors. RESULTS: Immunohistochemical staining showed that FLI1 is aberrantly overexpressed in advanced stage and metastatic breast cancers. Using a CRISPR Cas9-guided immunoprecipitation assay, we identify a circular RNA in the FLI1 promoter chromatin complex, consisting of FLI1 exons 4-2-3, referred to as FECR1...
December 11, 2018: Genome Biology
https://www.readbyqxmd.com/read/30537514/resistance-to-epigenetic-targeted-therapy-engenders-tumor-cell-vulnerabilities-associated-with-enhancer-remodeling
#2
Amanda Balboni Iniguez, Gabriela Alexe, Emily Jue Wang, Giovanni Roti, Sarvagna Patel, Liying Chen, Samuel Kitara, Amy Conway, Amanda L Robichaud, Björn Stolte, Pratiti Bandopadhayay, Amy Goodale, Sasha Pantel, Yenarae Lee, Dorian M Cheff, Matthew D Hall, Rajarshi Guha, Mindy I Davis, Marie Menard, Nicole Nasholm, William A Weiss, Jun Qi, Rameen Beroukhim, Federica Piccioni, Cory Johannessen, Kimberly Stegmaier
Drug resistance represents a major challenge to achieving durable responses to cancer therapeutics. Resistance mechanisms to epigenetically targeted drugs remain largely unexplored. We used bromodomain and extra-terminal domain (BET) inhibition in neuroblastoma as a prototype to model resistance to chromatin modulatory therapeutics. Genome-scale, pooled lentiviral open reading frame (ORF) and CRISPR knockout rescue screens nominated the phosphatidylinositol 3-kinase (PI3K) pathway as promoting resistance to BET inhibition...
December 10, 2018: Cancer Cell
https://www.readbyqxmd.com/read/30532595/cdk7-inhibition-is-a-novel-therapeutic-strategy-against-gbm-both-in-vitro-and-in-vivo
#3
Wei Meng, Jiajia Wang, Baocheng Wang, Fang Liu, Meng Li, Yang Zhao, Chenran Zhang, Qifeng Li, Juxiang Chen, Liye Zhang, Yujie Tang, Jie Ma
Background: Glioblastoma multiforme (GBM) remains to be one of the top lethal cancer types for adult to date. Current GBM therapies suffer greatly from the highly heterogeneous and adaptable nature of GBM cells, indicating an urgent need of alternative therapeutic options. In this study, we focused on identifying novel epigenetic targeted strategy against GBM. Methods: A collection of epigenetic modulating small molecules were subjected to anti-GBM screening and the inhibitory effect of identified agent was validated both in vitro and in vivo...
2018: Cancer Management and Research
https://www.readbyqxmd.com/read/30516846/hells-regulates-chromatin-remodeling-and-epigenetic-silencing-of-multiple-tumor-suppressor-genes-in-human-hepatocellular-carcinoma
#4
Cheuk-Ting Law, Lai Wei, Felice Ho-Ching Tsang, Cerise Yuen-Ki Chan, Iris Ming-Jing Xu, Robin Kit-Ho Lai, Daniel Wai-Hung Ho, Joyce Man-Fong Lee, Carmen Chak-Lui Wong, Irene Oi-Lin Ng, Chun-Ming Wong
Hepatocellular carcinoma (HCC) is the third lethal cancer worldwide. Increasing evidence showed that epigenetic alterations play an important role in human carcinogenesis. Deregulation of DNA methylation and histone modifications have recently been characterized in HCC, but the significance of chromatin remodeling in liver carcinogenesis remains to be explored. In this study, by systematically analyzing the expression of chromatin remodeling genes in human HCCs, we found that HELicase, Lymphoid-Specific (HELLS), a SWI2/SNF2 chromatin remodeling enzyme, was remarkably overexpressed in HCC...
December 5, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/30514438/histone-demethylase-kdm3b-regulates-the-transcriptional-network-of-cell-cycle-genes-in-hepatocarcinoma-hepg2-cells
#5
Mi-Jin An, Dae-Hyun Kim, Chul-Hong Kim, Mijin Kim, Sangmyung Rhee, Sang-Beom Seo, Jung-Woong Kim
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most lethal cancer worldwide. Although gene mutations associated with HCC development have been intensively studied, how epigenetic factors specifically modulate the functional properties of HCC by regulating target gene expression is unclear. Here we demonstrated the overexpression of KDM3B in liver tissue of HCC patients using public RNA-seq data. Ablation of KDM3B by CRISPR/Cas9 retarded the cell cycle and proliferation of hepatocarcinoma HepG2 cells...
December 1, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/30417100/tet2-coactivates-gene-expression-through-demethylation-of-enhancers
#6
Lu Wang, Patrick A Ozark, Edwin R Smith, Zibo Zhao, Stacy A Marshall, Emily J Rendleman, Andrea Piunti, Caila Ryan, Anna L Whelan, Kathryn A Helmin, Marc Alard Morgan, Lihua Zou, Benjamin D Singer, Ali Shilatifard
The tet methylcytosine dioxygenase 2 (TET2) enzyme catalyzes the conversion of the modified DNA base 5-methylcytosine to 5-hydroxymethylcytosine. TET2 is frequently mutated or dysregulated in multiple human cancers, and loss of TET2 is associated with changes in DNA methylation patterns. Here, using newly developed TET2-specific antibodies and the estrogen response as a model system for studying the regulation of gene expression, we demonstrate that endogenous TET2 occupies active enhancers and facilitates the proper recruitment of estrogen receptor α (ERα)...
November 2018: Science Advances
https://www.readbyqxmd.com/read/30233643/the-lysine-demethylase-dkdm2-is-non-essential-for-viability-but-regulates-circadian-rhythms-in-drosophila
#7
Yani Zheng, Yongbo Xue, Xingjie Ren, Mengmeng Liu, Xiao Li, Yu Jia, Ye Niu, Jian-Quan Ni, Yong Zhang, Jun-Yuan Ji
Post-translational modification of histones, such as histone methylation controlled by specific methyltransferases and demethylases, play critical roles in modulating chromatin dynamics and transcription in eukaryotes. Misregulation of histone methylation can lead to aberrant gene expression, thereby contributing to abnormal development and diseases such as cancer. As such, the mammalian lysine-specific demethylase 2 (KDM2) homologs, KDM2A and KDM2B, are either oncogenic or tumor suppressive depending on specific pathological contexts...
2018: Frontiers in Genetics
https://www.readbyqxmd.com/read/30214631/aspirin-cooperates-with-p300-to-activate-the-acetylation-of-h3k9-and-promote-fasl-mediated-apoptosis-of-cancer-stem-like-cells-in-colorectal-cancer
#8
Zhigang Chen, Wenlu Li, Fuming Qiu, Qi Huang, Zhou Jiang, Jun Ye, Pu Cheng, Cho Low, Yikun Guo, Xinchi Yi, Wenteng Chen, Yongpin Yu, YueHua Han, Jun Wu, Shenghang Jin, Dong Kong, Jian Huang
Cancer stem-like cells (CSCs) have been proposed as a key driving force of tumor growth and relapse in colorectal cancer (CRC), and therefore, they are promising targets for cancer therapy. Epidemiological evidence has suggested that the daily use of aspirin reduces overall mortality of CRC and the risk of distant metastasis. We investigated the effect and mechanism of aspirin on CSCs in CRC. Methods: The ratio of CSCs was analyzed after aspirin treatment both in a cell model and patient samples. Chemically modified aspirin and immunoprecipitation were adopted to detect the target proteins of aspirin...
2018: Theranostics
https://www.readbyqxmd.com/read/30096312/divergent-routes-toward-wnt-and-r-spondin-niche-independency-during-human-gastric-carcinogenesis
#9
Kosaku Nanki, Kohta Toshimitsu, Ai Takano, Masayuki Fujii, Mariko Shimokawa, Yuki Ohta, Mami Matano, Takashi Seino, Shingo Nishikori, Keiko Ishikawa, Kenta Kawasaki, Kazuhiro Togasaki, Sirirat Takahashi, Yasutaka Sukawa, Hiroki Ishida, Shinya Sugimoto, Hirofumi Kawakubo, Jihoon Kim, Yuko Kitagawa, Shigeki Sekine, Bon-Kyoung Koo, Takanori Kanai, Toshiro Sato
Recent sequencing analyses have shed light on heterogeneous patterns of genomic aberrations in human gastric cancers (GCs). To explore how individual genetic events translate into cancer phenotypes, we established a biological library consisting of genetically engineered gastric organoids carrying various GC mutations and 37 patient-derived organoid lines, including rare genomically stable GCs. Phenotype analyses of GC organoids revealed divergent genetic and epigenetic routes to gain Wnt and R-spondin niche independency...
August 9, 2018: Cell
https://www.readbyqxmd.com/read/30082728/trps1-shapes-yap-tead-dependent-transcription-in-breast-cancer-cells
#10
Dana Elster, Marie Tollot, Karin Schlegelmilch, Alessandro Ori, Andreas Rosenwald, Erik Sahai, Björn von Eyss
Yes-associated protein (YAP), the downstream transducer of the Hippo pathway, is a key regulator of organ size, differentiation and tumorigenesis. To uncover Hippo-independent YAP regulators, we performed a genome-wide CRISPR screen that identifies the transcriptional repressor protein Trichorhinophalangeal Syndrome 1 (TRPS1) as a potent repressor of YAP-dependent transactivation. We show that TRPS1 globally regulates YAP-dependent transcription by binding to a large set of joint genomic sites, mainly enhancers...
August 6, 2018: Nature Communications
https://www.readbyqxmd.com/read/29914980/epigenetic-regulators-rbbp4-and-hdac1-are-overexpressed-in-a-zebrafish-model-of-rb1-embryonal-brain-tumor-and-are-required-for-neural-progenitor-survival-and-proliferation
#11
Laura E Schultz, Jeffrey A Haltom, Maira P Almeida, Wesley A Wierson, Staci L Solin, Trevor J Weiss, Jordan A Helmer, Elizabeth J Sandquist, Heather R Shive, Maura McGrail
In this study, we used comparative genomics and developmental genetics to identify epigenetic regulators driving oncogenesis in a zebrafish retinoblastoma 1 ( rb1 ) somatic-targeting model of RB1 mutant embryonal brain tumors. Zebrafish rb1 brain tumors caused by TALEN or CRISPR targeting are histologically similar to human central nervous system primitive neuroectodermal tumors (CNS-PNETs). Like the human oligoneural OLIG2+/SOX10+ CNS-PNET subtype, zebrafish rb1 tumors show elevated expression of neural progenitor transcription factors olig2 , sox10 , sox8b and the receptor tyrosine kinase erbb3a oncogene...
June 15, 2018: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29899406/lactb-a-novel-epigenetic-silenced-tumor-suppressor-inhibits-colorectal-cancer-progression-by-attenuating-mdm2-mediated-p53-ubiquitination-and-degradation
#12
Kaixuan Zeng, Xiaoxiang Chen, Xiuxiu Hu, Xiangxiang Liu, Tao Xu, Huiling Sun, Yuqin Pan, Bangshun He, Shukui Wang
Colorectal cancer (CRC) is one of the most common aggressive malignancies. Like other solid tumors, inactivation of tumor suppressor genes and activation of oncogenes occur during CRC development and progression. Recently, a novel tumor suppressor, LACTB, was proposed to inhibit tumor progression, but the functional and clinical significance of this tumor suppressor in CRC remains unexplored. Herein, we found LACTB was significantly downregulated in CRC due to promoter methylation and histone deacetylation, which was associated with metastasis and advanced clinical stage...
June 13, 2018: Oncogene
https://www.readbyqxmd.com/read/29858058/epigenetic-targeting-of-granulin-in-hepatoma-cells-by-synthetic-crispr-dcas9-epi-suppressors
#13
Hong Wang, Rui Guo, Zhonghua Du, Ling Bai, Lingyu Li, Jiuwei Cui, Wei Li, Andrew R Hoffman, Ji-Fan Hu
The CRISPR-associated Cas9 system can modulate disease-causing alleles both in vivo and ex vivo, raising the possibility of therapeutic genome editing. In addition to gene targeting, epigenetic modulation by the catalytically inactive dCas9 may also be a potential form of cancer therapy. Granulin (GRN), a potent pluripotent mitogen and growth factor that promotes cancer progression by maintaining self-renewal of hepatic stem cancer cells, is upregulated in hepatoma tissues and is associated with decreased tumor survival in patients with hepatoma...
June 1, 2018: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/29778644/a-trichostatin-a-tsa-sp1-mediated-mechanism-for-the-regulation-of-sall2-tumor-suppressor-in-jurkat-t-cells
#14
Matías I Hepp, David Escobar, Carlos Farkas, Viviana E Hermosilla, Claudia Álvarez, Roberto Amigo, José L Gutiérrez, Ariel F Castro, Roxana Pincheira
SALL2 is a transcription factor involved in development and disease. Deregulation of SALL2 has been associated with cancer, suggesting that it plays a role in the disease. However, how SALL2 is regulated and why is deregulated in cancer remain poorly understood. We previously showed that the p53 tumor suppressor represses SALL2 under acute genotoxic stress. Here, we investigated the effect of Histone Deacetylase Inhibitor (HDACi) Trichostatin A (TSA), and involvement of Sp1 on expression and function of SALL2 in Jurkat T cells...
May 18, 2018: Biochimica et biophysica acta. Gene regulatory mechanisms
https://www.readbyqxmd.com/read/29700004/phf5a-epigenetically-inhibits-apoptosis-to-promote-breast-cancer-progression
#15
Yi-Zi Zheng, Meng-Zhu Xue, Hong-Jie Shen, Xiao-Guang Li, Ding Ma, Yue Gong, Yi-Rong Liu, Feng Qiao, Hong-Yan Xie, Bi Lian, Wei-Li Sun, Hai-Yun Zhao, Ling Yao, Wen-Jia Zuo, Da-Qiang Li, Peng Wang, Xin Hu, Zhi-Ming Shao
Alternative splicing (AS) and its regulation play critical roles in cancer, yet the dysregulation of AS and its molecular bases in breast cancer development have not yet been elucidated. Using an in vivo CRISPR screen targeting RNA-binding proteins, we identified PHD finger protein 5A (PHF5A) as a key splicing factor involved in tumor progression. PHF5A expression was frequently upregulated in breast cancer and correlated with poor survival, and knockdown of PHF5A significantly suppressed cell proliferation, migration, and tumor formation...
June 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29666172/genetic-editing-of-colonic-organoids-provides-a-molecularly-distinct-and-orthotopic-preclinical-model-of-serrated-carcinogenesis
#16
Tamsin R M Lannagan, Young K Lee, Tongtong Wang, Jatin Roper, Mark L Bettington, Lochlan Fennell, Laura Vrbanac, Lisa Jonavicius, Roshini Somashekar, Krystyna Gieniec, Miao Yang, Jia Q Ng, Nobumi Suzuki, Mari Ichinose, Josephine A Wright, Hiroki Kobayashi, Tracey L Putoczki, Yoku Hayakawa, Simon J Leedham, Helen E Abud, Ömer H Yilmaz, Julie Marker, Sonja Klebe, Pratyaksha Wirapati, Siddhartha Mukherjee, Sabine Tejpar, Barbara A Leggett, Vicki L J Whitehall, Daniel L Worthley, Susan L Woods
OBJECTIVE: Serrated colorectal cancer (CRC) accounts for approximately 25% of cases and includes tumours that are among the most treatment resistant and with worst outcomes. This CRC subtype is associated with activating mutations in the mitogen-activated kinase pathway gene, BRAF , and epigenetic modifications termed the CpG Island Methylator Phenotype, leading to epigenetic silencing of key tumour suppressor genes. It is still not clear which (epi-)genetic changes are most important in neoplastic progression and we begin to address this knowledge gap herein...
April 17, 2018: Gut
https://www.readbyqxmd.com/read/29572228/transition-of-mesenchymal-and-epithelial-cancer-cells-depends-on-%C3%AE-1-4-galactosyltransferase-mediated-glycosphingolipids
#17
Francis Jacob, Shahidul Alam, Martina Konantz, Ching-Yeu Liang, Reto S Kohler, Arun V Everest-Dass, Yen-Lin Huang, Natalie Rimmer, Andre Fedier, Andreas Schötzau, Monica Nunez Lopez, Nicolle H Packer, Claudia Lengerke, Viola Heinzelmann-Schwarz
The reversible transitions of cancer cells between epithelial and mesenchymal states comprise cellular and molecular processes essential for local tumor growth and respective dissemination. We report here that globoside glycosphingolipid (GSL) glycosyltransferase-encoding genes are elevated in epithelial cells and correlate with characteristic EMT signatures predictive of disease outcome. Depletion of globosides through CRISPR- Cas9 -mediated deletion of the key enzyme A4GALT induces EMT, enhances chemoresistance, and increased CD24low /CD44high cells...
June 1, 2018: Cancer Research
https://www.readbyqxmd.com/read/29555645/epigenetic-silencing-of-mir-125b-is-required-for-normal-b-cell-development
#18
Guideng Li, Alex Yick-Lun So, Reeshelle Sookram, Stephanie Wong, Jessica K Wang, Yong Ouyang, Peng He, Yapeng Su, Rafael Casellas, David Baltimore
Deregulation of several microRNAs (miRs) can influence critical developmental checkpoints during hematopoiesis as well as cell functions, eventually leading to the development of autoimmune disease or cancer. We found that miR-125b is expressed in bone marrow multipotent progenitors and myeloid cells but shut down in the B-cell lineage, and the gene encoding miR-125b lacked transcriptional activation markers in B cells. To understand the biological importance of the physiological silencing of miR-125b expression in B cells, we drove its expression in the B-cell lineage and found that dysregulated miR-125b expression impaired egress of immature B cells from the bone marrow to peripheral blood...
April 26, 2018: Blood
https://www.readbyqxmd.com/read/29524149/editing-of-dna-methylation-using-dcas9-peptide-repeat-and-scfv-tet1-catalytic-domain-fusions
#19
Sumiyo Morita, Takuro Horii, Izuho Hatada
DNA methylation, one of the most studied epigenetic modifications, regulates many biological processes. Dysregulation of DNA methylation is implicated in the etiology of several diseases, such as cancer and imprinting diseases. Accordingly, technologies designed to manipulate DNA methylation at specific loci are very important, and many epigenome editing technologies have been developed, based on zinc finger proteins, TALEs, and CRISPR/dCas9 targeting. We describe a protocol to induce and assess DNA demethylation on a target gene...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29433054/hallmarks-of-cancer-the-crispr-generation
#20
REVIEW
Colette Moses, Benjamin Garcia-Bloj, Alan R Harvey, Pilar Blancafort
The hallmarks of cancer were proposed as a logical framework to guide research efforts that aim to understand the molecular mechanisms and derive treatments for this highly complex disease. Recent technological advances, including comprehensive sequencing of different cancer subtypes, have illuminated how genetic and epigenetic alterations are associated with specific hallmarks of cancer. However, as these associations are purely descriptive, one particularly exciting development is the emergence of genome editing technologies, which enable rapid generation of precise genetic and epigenetic modifications to assess the consequences of these perturbations on the cancer phenotype...
April 2018: European Journal of Cancer
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