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CRISPR AND epigenetic AND Cancer

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https://www.readbyqxmd.com/read/30096312/divergent-routes-toward-wnt-and-r-spondin-niche-independency-during-human-gastric-carcinogenesis
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
https://www.readbyqxmd.com/read/29700004/phf5a-epigenetically-inhibits-apoptosis-to-promote-breast-cancer-progression
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/29368602/long-non-coding-rna-implicated-in-the-invasion-and-metastasis-of-head-and-neck-cancer-possible-function-and-mechanisms
#13
REVIEW
Xiaobo Luo, Yan Qiu, Yuchen Jiang, Fangman Chen, Lu Jiang, Yu Zhou, Hongxia Dan, Xin Zeng, Yu L Lei, Qianming Chen
Head and neck cancer (HNC) ranks as the 6th most common malignancy across the world. Metastasis is a hallmark of cancer, primarily contributing to the relapse and poor prognosis of HNC. Recently, long noncoding RNAs (lncRNAs), previously considered as non-functional, are increasingly appreciated by scholars to play crucial roles in mediating HNC metastasis. LncRNAs, which are located in the nucleus and cytoplasm, mainly exert their function via epigenetic modification, transcriptional control and translational regulation...
January 24, 2018: Molecular Cancer
https://www.readbyqxmd.com/read/29330288/epigenetically-regulated-chromosome-14q32-mirna-cluster-induces-metastasis-and-predicts-poor-prognosis-in-lung-adenocarcinoma-patients
#14
Margarita González-Vallinas, Manuel Rodríguez-Paredes, Marco Albrecht, Carsten Sticht, Damian Stichel, Julian Gutekunst, Adriana Pitea, Steffen Sass, Francisco J Sánchez-Rivera, Justo Lorenzo-Bermejo, Jennifer Schmitt, Carolina De La Torre, Arne Warth, Fabian J Theis, Nikola S Müller, Norbert Gretz, Thomas Muley, Michael Meister, Darjus F Tschaharganeh, Peter Schirmacher, Franziska Matthäus, Kai Breuhahn
Most lung cancer deaths are related to metastases, which indicates the necessity of detecting and inhibiting tumor cell dissemination. Here, we aimed to identify miRNAs involved in metastasis of lung adenocarcinoma as prognostic biomarkers and therapeutic targets. To that end, lymph node metastasis-associated miRNAs were identified in The Cancer Genome Atlas lung adenocarcinoma patient cohort (sequencing data; n = 449) and subsequently validated by qRT-PCR in an independent clinical cohort ( n = 108). Overexpression of miRNAs located on chromosome 14q32 was associated with metastasis in lung adenocarcinoma patients...
March 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29259014/er-stress-signaling-promotes-the-survival-of-cancer-persister-cells-tolerant-to-egfr-tyrosine-kinase-inhibitors
#15
Hideki Terai, Shunsuke Kitajima, Danielle S Potter, Yusuke Matsui, Laura Gutierrez Quiceno, Ting Chen, Tae-Jung Kim, Maria Rusan, Tran C Thai, Federica Piccioni, Katherine A Donovan, Nicholas Kwiatkowski, Kunihiko Hinohara, Guo Wei, Nathanael S Gray, Eric S Fischer, Kwok-Kin Wong, Teppei Shimamura, Anthony Letai, Peter S Hammerman, David A Barbie
An increasingly recognized component of resistance to tyrosine kinase inhibitors (TKI) involves persistence of a drug-tolerant subpopulation of cancer cells that survive despite effective eradication of the majority of the cell population. Multiple groups have demonstrated that these drug-tolerant persister cells undergo transcriptional adaptation via an epigenetic state change that promotes cell survival. Because this mode of TKI drug tolerance appears to involve transcriptional addiction to specific genes and pathways, we hypothesized that systematic functional screening of EGFR TKI/transcriptional inhibitor combination therapy would yield important mechanistic insights and alternative drug escape pathways...
February 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29229993/therapeutic-relevance-of-the-pp2a-b55-inhibitory-kinase-mastl-greatwall-in-breast-cancer
#16
Mónica Álvarez-Fernández, María Sanz-Flores, Belén Sanz-Castillo, María Salazar-Roa, David Partida, Elisabet Zapatero-Solana, H Raza Ali, Eusebio Manchado, Scott Lowe, Todd VanArsdale, David Shields, Carlos Caldas, Miguel Quintela-Fandino, Marcos Malumbres
PP2A is a major tumor suppressor whose inactivation is frequently found in a wide spectrum of human tumors. In particular, deletion or epigenetic silencing of genes encoding the B55 family of PP2A regulatory subunits is a common feature of breast cancer cells. A key player in the regulation of PP2A/B55 phosphatase complexes is the cell cycle kinase MASTL (also known as Greatwall). During cell division, inhibition of PP2A-B55 by MASTL is required to maintain the mitotic state, whereas inactivation of MASTL and PP2A reactivation is required for mitotic exit...
May 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29202477/crispr-cas9-screen-reveals-a-mycn-amplified-neuroblastoma-dependency-on-ezh2
#17
Liying Chen, Gabriela Alexe, Neekesh V Dharia, Linda Ross, Amanda Balboni Iniguez, Amy Saur Conway, Emily Jue Wang, Veronica Veschi, Norris Lam, Jun Qi, W Clay Gustafson, Nicole Nasholm, Francisca Vazquez, Barbara A Weir, Glenn S Cowley, Levi D Ali, Sasha Pantel, Guozhi Jiang, William F Harrington, Yenarae Lee, Amy Goodale, Rakela Lubonja, John M Krill-Burger, Robin M Meyers, Aviad Tsherniak, David E Root, James E Bradner, Todd R Golub, Charles Wm Roberts, William C Hahn, William A Weiss, Carol J Thiele, Kimberly Stegmaier
Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy. For the childhood cancer neuroblastoma, amplification of the oncogene MYCN is associated with high-risk disease and poor prognosis. Here, we deployed genome-scale CRISPR-Cas9 screening of MYCN-amplified neuroblastoma and found a preferential dependency on genes encoding the polycomb repressive complex 2 (PRC2) components EZH2, EED, and SUZ12. Genetic and pharmacological suppression of EZH2 inhibited neuroblastoma growth in vitro and in vivo...
January 2, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29179174/-current-advances-and-future-prospects-of-genome-editing-technology-in-the-field-of-biomedicine
#18
Tetsushi Sakuma
Genome editing technology can alter the genomic sequence at will, contributing the creation of cellular and animal models of human diseases including hereditary disorders and cancers, and the generation of the mutation-corrected human induced pluripotent stem cells for ex vivo regenerative medicine. In addition, novel approaches such as drug development using genome-wide CRISPR screening and cancer suppression using epigenome editing technology, which can change the epigenetic modifications in a site-specific manner, have also been conducted...
2017: Clinical Calcium
https://www.readbyqxmd.com/read/29171881/rna-n6-methyladenosine-methyltransferase-like-3-promotes-liver-cancer-progression-through-ythdf2-dependent-posttranscriptional-silencing-of-socs2
#19
Mengnuo Chen, Lai Wei, Cheuk-Ting Law, Felice Ho-Ching Tsang, Jialing Shen, Carol Lai-Hung Cheng, Long-Hin Tsang, Daniel Wai-Hung Ho, David Kung-Chun Chiu, Joyce Man-Fong Lee, Carmen Chak-Lui Wong, Irene Oi-Lin Ng, Chun-Ming Wong
Epigenetic alterations have contributed greatly to human carcinogenesis. Conventional epigenetic studies have predominantly focused on DNA methylation, histone modifications, and chromatin remodeling. Recently, diverse and reversible chemical modifications of RNAs have emerged as a new layer of epigenetic regulation. N6-methyladenosine (m6A) is the most abundant chemical modification of eukaryotic messenger RNA (mRNA) and is important for the regulation of mRNA stability, splicing, and translation. Using transcriptome sequencing, we discovered that methyltransferase-like 3 (METTL3), a major RNA N6-adenosine methyltransferase, was significantly up-regulated in human hepatocellular carcinoma (HCC) and multiple solid tumors...
June 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29133799/hit-and-run-epigenetic-editing-prevents-senescence-entry-in-primary-breast-cells-from-healthy-donors
#20
Emily A Saunderson, Peter Stepper, Jennifer J Gomm, Lily Hoa, Adrienne Morgan, Michael D Allen, J Louise Jones, John G Gribben, Tomasz P Jurkowski, Gabriella Ficz
Aberrant promoter DNA hypermethylation is a hallmark of cancer; however, whether this is sufficient to drive cellular transformation is not clear. To investigate this question, we use a CRISPR-dCas9 epigenetic editing tool, where an inactive form of Cas9 is fused to DNA methyltransferase effectors. Using this system, here we show simultaneous de novo DNA methylation of genes commonly methylated in cancer, CDKN2A, RASSF1, HIC1 and PTEN in primary breast cells isolated from healthy human breast tissue. We find that promoter methylation is maintained in this system, even in the absence of the fusion construct, and this prevents cells from engaging senescence arrest...
November 13, 2017: Nature Communications
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