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    Waking up dormant tumor suppressor genes with zinc fingers, TALEs and the CRISPR/dCas9 system

    246354_246354.pdf (6.048Mb)
    Access Status
    Open access
    Authors
    Garcia-Bloj, B.
    Moses, C.
    Sgro, A.
    Plani-Lam, J.
    Arooj, Mahira
    Duffy, C.
    Thiruvengadam, S.
    Sorolla, A.
    Rashwan, R.
    Mancera, Ricardo
    Leisewitz, A.
    Swift-Scanlan, T.
    Corvalan, A.
    Blancafort, P.
    Date
    2016
    Type
    Journal Article
    
    Metadata
    Show full item record
    Citation
    Garcia-Bloj, B. and Moses, C. and Sgro, A. and Plani-Lam, J. and Arooj, M. and Duffy, C. and Thiruvengadam, S. et al. 2016. Waking up dormant tumor suppressor genes with zinc fingers, TALEs and the CRISPR/dCas9 system. Oncotarget. 7 (37): pp. 60535-60554.
    Source Title
    Oncotarget
    DOI
    10.18632/oncotarget.11142
    School
    School of Biomedical Sciences
    Remarks

    This open access article is distributed under the Creative Commons license http://creativecommons.org/licenses/by/3.0/

    URI
    http://hdl.handle.net/20.500.11937/22885
    Collection
    • Curtin Research Publications
    Abstract

    The aberrant epigenetic silencing of tumor suppressor genes (TSGs) plays a major role during carcinogenesis and regaining these dormant functions by engineering of sequence-specific epigenome editing tools offers a unique opportunity for targeted therapies. However, effectively normalizing the expression and regaining tumor suppressive functions of silenced TSGs by artificial transcription factors (ATFs) still remains a major challenge. Herein we describe novel combinatorial strategies for the potent reactivation of two class II TSGs, MASPIN and REPRIMO, in cell lines with varying epigenetic states, using the CRISPR/dCas9 associated system linked to a panel of effector domains (VP64, p300, VPR and SAM complex), as well as with protein-based ATFs, Zinc Fingers and TALEs. We found that co-delivery of multiple effector domains using a combination of CRISPR/dCas9 and TALEs or SAM complex maximized activation in highly methylated promoters. In particular, CRISPR/dCas9 VPR with SAM upregulated MASPIN mRNA (22,145-fold change) in H157 lung cancer cells, with accompanying re-expression of MASPIN protein, which led to a concomitant inhibition of cell proliferation and induction of apoptotic cell death. Consistently, CRISPR/dCas9 VP64 with SAM upregulated REPRIMO (680-fold change), which led to phenotypic reprogramming in AGS gastric cancer cells. Altogether, our results outlined novel sequence-specific, combinatorial epigenome editing approaches to reactivate highly methylated TSGs as a promising therapy for cancer and other diseases.

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