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      Epigenetic reactivation of LINE‐1 retrotransposon disrupts NuRD corepressor functions and induces oncogenic transformation in human bronchial epithelial cells

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          Abstract

          Long interspersed nuclear element‐1 ( LINE‐1 or L1) reactivation is linked to poor prognosis in non‐small‐cell lung carcinoma ( NSCLC), but the molecular bases of this response remain largely unknown. In this report, we show that challenge of human bronchial epithelial cells ( HBECs) with the lung carcinogen, benzo(a)pyrene (BaP), shifted the L1 promoter from a heterochromatic to euchromatic state through disassembly of the nucleosomal and remodeling deacetylase (Nu RD) complex. Carcinogen challenge was also associated with partial displacement of constituent proteins from the nuclear to the cytoplasmic compartment. Disruption of Nu RD corepression by genetic ablation or carcinogen treatment correlated with accumulation of L1 mRNA and proteins. Mi2β bound directly to the L1 promoter to effect retroelement silencing, and this response required the DNA‐ and ATPase‐binding domains of Mi2β. Sustained expression of L1 in HBECs was tumorigenic in a human– SCID mouse xenograft model, giving rise to tumors that regressed over time. Together, these results show that functional modulation of the Nu RD constituent proteins is a critical molecular event in the activation of L1 retrotransposon. L1 expression creates a microenvironment in HBECs that is conducive to neoplasia and malignant transformation.

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          The significance of responses of the genome to challenge.

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            Human L1 retrotransposition: cis preference versus trans complementation.

            Long interspersed nuclear elements (LINEs or L1s) comprise approximately 17% of human DNA; however, only about 60 of the approximately 400,000 L1s are mobile. Using a retrotransposition assay in cultured human cells, we demonstrate that L1-encoded proteins predominantly mobilize the RNA that encodes them. At much lower levels, L1-encoded proteins can act in trans to promote retrotransposition of mutant L1s and other cellular mRNAs, creating processed pseudogenes. Mutant L1 RNAs are mobilized at 0.2 to 0.9% of the retrotransposition frequency of wild-type L1s, whereas cellular RNAs are mobilized at much lower frequencies (ca. 0.01 to 0.05% of wild-type levels). Thus, we conclude that L1-encoded proteins demonstrate a profound cis preference for their encoding RNA. This mechanism could enable L1 to remain retrotransposition competent in the presence of the overwhelming number of nonfunctional L1s present in human DNA.
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              LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer.

              Lysine-specific demethylase 1 (LSD1) exerts pathway-specific activity in animal development and has been linked to several high-risk cancers. Here, we report that LSD1 is an integral component of the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex. Transcriptional target analysis revealed that the LSD1/NuRD complexes regulate several cellular signaling pathways including TGFbeta1 signaling pathway that are critically involved in cell proliferation, survival, and epithelial-to-mesenchymal transition. We demonstrated that LSD1 inhibits the invasion of breast cancer cells in vitro and suppresses breast cancer metastatic potential in vivo. We found that LSD1 is downregulated in breast carcinomas and that its level of expression is negatively correlated with that of TGFbeta1. Our data provide a molecular basis for the interplay of histone demethylation and deacetylation in chromatin remodeling. By enlisting LSD1, the NuRD complex expands its chromatin remodeling capacity to include ATPase, histone deacetylase, and histone demethylase.
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                Author and article information

                Contributors
                ksramos@email.arizona.edu
                Journal
                Mol Oncol
                Mol Oncol
                10.1002/(ISSN)1878-0261
                MOL2
                Molecular Oncology
                John Wiley and Sons Inc. (Hoboken )
                1574-7891
                1878-0261
                21 June 2018
                August 2018
                : 12
                : 8 ( doiID: 10.1002/mol2.2018.12.issue-8 )
                : 1342-1357
                Affiliations
                [ 1 ] Division of Pulmonary, Allergy, Critical Care and Sleep Medicine University of Arizona College of Medicine Tucson AZ USA
                [ 2 ] Center for Applied Genetics and Genomic Medicine University of Arizona Health Sciences Tucson AZ USA
                Author notes
                [*] [* ] Correspondence

                K. S. Ramos, Department of Medicine, University of Arizona College of Medicine, Tucson, AZ 85721, USA

                E‐mail: ksramos@ 123456email.arizona.edu

                Article
                MOL212329
                10.1002/1878-0261.12329
                6068357
                29845737
                9d4785d1-0866-4cac-9307-444be65dab54
                © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 January 2018
                : 01 May 2018
                : 01 May 2018
                Page count
                Figures: 7, Tables: 5, Pages: 16, Words: 9269
                Funding
                Funded by: University of Arizona Health Sciences
                Award ID: P30 CA023074
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                mol212329
                August 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:01.08.2018

                Oncology & Radiotherapy
                benzo(a)pyrene,euchromatin,heterochromatin,long interspersed nuclear element‐1,nucleosomal and remodeling deacetylase complex,retrotransposon

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