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CRISPR AND epigenetic AND Cancer

Di Qu, Wei-Wei Sun, Li Li, Li Ma, Li Sun, Xia Jin, Taisheng Li, Wei Hou, Jian-Hua Wang
Long noncoding RNAs (lncRNAs) may either repress or activate HIV-1 replication and latency; however, specific mechanisms for their action are not always clear. In HIV-1 infected CD4+ T cells, we performed RNA-Sequencing (RNA-Seq) analysis and discovered an up-regulation of MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), an lncRNA previously described in cancer cells that associate with cancer pathogenesis. Moreover, we found that MALAT1 promoted HIV-1 transcription and infection, as its knockdown by CRISPR/Cas9 markedly reduced the HIV-1 long terminal repeat (LTR)-driven gene transcription and viral replication...
February 21, 2019: Nucleic Acids Research
Sarah C Pyfrom, Hong Luo, Jacqueline E Payton
BACKGROUND: Long non-coding RNAs (lncRNAs) exhibit remarkable cell-type specificity and disease association. LncRNA's functional versatility includes epigenetic modification, nuclear domain organization, transcriptional control, regulation of RNA splicing and translation, and modulation of protein activity. However, most lncRNAs remain uncharacterized due to a shortage of predictive tools available to guide functional experiments. RESULTS: To address this gap for lymphoma-associated lncRNAs identified in our studies, we developed a new computational method, Predicting LncRNA Activity through Integrative Data-driven 'Omics and Heuristics (PLAIDOH), which has several unique features not found in other methods...
February 15, 2019: BMC Genomics
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
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
Minjiang Chen, Aiwu Mao, Min Xu, Qiaoyou Weng, Jianting Mao, Jiansong Ji
Cancer is a genetic disease stemming from cumulative genetic/epigenetic aberrations. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9-mediated genome editing technology has been extensively applied in various cell types and organisms, both in vitro and in vivo, for efficient gene disruption and gene modification. CRISPR-Cas9 has shown great promise for the treatment of cancer. However, despite its advantages and tremendous potential, numerous challenges, such as fitness of edited cells, editing efficiency, delivery methods and potential off-target effects, remain to be solved for completely clinical application...
January 23, 2019: Cancer Letters
Colette Moses, Fiona Nugent, Charlene Babra Waryah, Benjamin Garcia-Bloj, Alan R Harvey, Pilar Blancafort
PTEN expression is lost in many cancers, and even small changes in PTEN activity affect susceptibility and prognosis in a range of highly aggressive malignancies, such as melanoma and triple-negative breast cancer (TNBC). Loss of PTEN expression occurs via multiple mechanisms, including mutation, transcriptional repression and epigenetic silencing. Transcriptional repression of PTEN contributes to resistance to inhibitors used in the clinic, such as B-Raf inhibitors in BRAF mutant melanoma. We aimed to activate PTEN expression using the CRISPR system, specifically dead (d) Cas9 fused to the transactivator VP64-p65-Rta (VPR)...
December 14, 2018: Molecular Therapy. Nucleic Acids
Aixia Sui, Yongbing Xu, Junjie Yang, Baogen Pan, Jiang Wu, Tao Guo, Yongqing Shen, Xiaoqiang Guo
The histone demethylase KDM6B, also known as jumonji domain-containing protein 3 (JMJD3), is an epigenetic regulator which plays important roles in immune activation, tissue regeneration, cellular senescence and cancer metastasis. But, the role of KDM6B in glioma metastasis is poorly understood. In this study, we achieved transcriptional regulation of KDM6B in glioma cells using CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa). Our results showed that KDM6B promotes the proliferation, migration and invasion of human glioblastoma cells U87 and U251 using CCK8, scratch and transwell assays...
March 2019: Neurochemistry International
Yi Xiang See, Benny Zhengjie Wang, Melissa J Fullwood
Chromatin interactions regulate gene expression by bringing distal regulatory elements, such as super-enhancers, to promoters in close spatial proximity. It has been recognized that in cancer, chromatin interactions can be dysregulated, leading to aberrant oncogene expression. Chromatin interactions may potentially serve as biomarkers, or be modulated via CRISPR therapy and small molecule inhibitors against transcription. However, these methods face challenges that must be resolved and raise questions for further research...
February 2019: Trends in Genetics: TIG
Shuichi Watanabe, Shu Shimada, Yoshimitsu Akiyama, Yoshiya Ishikawa, Toshiro Ogura, Kosuke Ogawa, Hiroaki Ono, Yusuke Mitsunori, Daisuke Ban, Atsushi Kudo, Shoji Yamaoka, Minoru Tanabe, Shinji Tanaka
Although genomic analysis have recently discovered the malignant subtype of human pancreatic ductal adenocarcinoma (PDAC) characterized by frequent mutations of histone demethylase KDM6A, the biological and molecular roles still remain obscure. We herein elucidated the clinical and biological impacts of KDM6A deficiency on human PDAC and identified the therapeutic potential by pathological and molecular evaluation. Immunohistochemical analysis suggested that loss of KDM6A in cancerous tissues was an independent prognostic factor for both recurrence-free and overall survival in the 103 tumor specimens surgically resected from patients with PDAC...
December 17, 2018: International Journal of Cancer. Journal International du Cancer
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
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
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
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
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
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
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
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
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
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
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
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