Targeting Serous Epithelial Ovarian Cancer with Designer Zinc Finger Transcription Factors

Lara, Haydee; Wang, Yuhua; Beltran, Adriana S.; Juárez-Moreno, Karla; Yuan, Xinni; Kato, Sumie; Leisewitz, Andrea V.; Fredes, Mauricio Cuello; Licea-Navarro, Alexei F.; Connolly, Denise C.; Huang, Leaf; Blancafort, Pilar

doi:10.1074/jbc.m112.360768

Cited by 41 publications

(33 citation statements)

References 73 publications

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“…As DNA-targeting tools, engineered zinc finger proteins (ZFP) have shown great flexibility in gene targeting (20). Modulation of expression of various endogenous genes has been achieved with upregulation of C13ORF18 (21), Maspin (22), down/upregulation of EpCAM (23), and downregulation of SOX2 (24) as some examples. Also, regulation of the Her2/neu gene expression has been achieved by ATFs (25,26), resulting in a satisfactory downregulation associated with cell growth inhibition (25).…”

Section: Introductionmentioning

confidence: 99%

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

Falahi

Huisman

Kazemier

et al. 2013

Molecular Cancer Research

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The human epidermal growth factor receptor-2 (HER2/neu/ERBB2) is overexpressed in several cancer types. Although therapies targeting the HER2/neu protein result in inhibition of cell proliferation, the anticancer effect might be further optimized by limiting HER2/neu expression at the DNA level. Towards this aim, epigenetic editing was performed to suppress HER2/neu expression by inducing epigenetic silencing marks on the HER2/neu promoter.HER2/neu expression and HER2/neu promoter epigenetic modification status were determined in a panel of ovarian and breast cancer cell lines. HER2/neu-overexpressing cancer cells were transduced to express a zinc finger protein (ZFP), targeting the HER2/neu gene, fused to histone methyltransferases (G9a, SUV39-H1)/super KRAB domain (SKD). Epigenetic assessment of the HER2/neu promoter showed that HER2/neu-ZFP fused to G9a efficiently induced the intended silencing histone methylation mark (H3K9me2). Importantly, H3K9me2 induction was associated with a dramatic downregulation of HER2/neu expression in HER2/neu-overexpressing cells. Downregulation by SKD, traditionally considered transient in nature, was associated with removal of the histone acetylation mark (H3ac). The downregulation of HER2/neu by induced H3K9 methylation and/or reduced H3 acetylation was sufficient to effectively inhibit cellular metabolic activity and clonogenicity. Furthermore, genome-wide analysis indicated preferential binding of the ZFP to its target sequence. These results not only show that H3K9 methylation can be induced but also that this epigenetic mark was instructive in promoting downregulation of HER2/neu expression.

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Section: Introductionmentioning

confidence: 99%

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

Falahi

Huisman

Kazemier

et al. 2013

Molecular Cancer Research

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“…It has been reported previously that maspin triggers several cellular processes which get reflected on cell behavior and cytoskeletal architecture (Odero-Marah et al, 2003;Qin & Zhang, 2010;Lara et al, 2012;Al-Mamun et al, 2016a). In a recent attempt, Al-Mamun et al, (2016b) showed that an image processing tool can be used to quantify three cellular parts: nuclei, cytoplasm and ruffling regions to observe the changes in shape and behavior.…”

Section: Discussionmentioning

confidence: 99%

A quantitative image analysis for the cellular cytoskeleton during in vitro tumor growth

Al-Mamun

Srisukkham

Farid

et al. 2018

Expert Systems with Applications

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“…The precise genetic repression of detrimental genes may be a useful strategy to mitigate pathology, such as repressing the huntingtin GUIDE-seq Digenome-seq (Kim et al 2015) BLESS (Ran et al 2015) DNase-seq/ATAC-seq gene for Huntington's disease (Garriga-Canut et al 2012). Similarly, targeted activation of aberrantly silenced endogenous loci may provide therapeutic benefits (Lara et al 2012). Additionally, the manipulation of irregular epigenetic modifications or genomic contacts could be useful to prevent or correct disease states.…”

Section: Genome Engineering To Model Disease and Develop Therapeuticsmentioning

confidence: 99%

Enabling functional genomics with genome engineering

Hilton

Gersbach

2015

Genome Res.

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Advances in genome engineering technologies have made the precise control over genome sequence and regulation possible across a variety of disciplines. These tools can expand our understanding of fundamental biological processes and create new opportunities for therapeutic designs. The rapid evolution of these methods has also catalyzed a new era of genomics that includes multiple approaches to functionally characterize and manipulate the regulation of genomic information. Here, we review the recent advances of the most widely adopted genome engineering platforms and their application to functional genomics. This includes engineered zinc finger proteins, TALEs/TALENs, and the CRISPR/Cas9 system as nucleases for genome editing, transcription factors for epigenome editing, and other emerging applications. We also present current and potential future applications of these tools, as well as their current limitations and areas for future advances.

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Targeting Serous Epithelial Ovarian Cancer with Designer Zinc Finger Transcription Factors

Cited by 41 publications

References 73 publications

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

A quantitative image analysis for the cellular cytoskeleton during in vitro tumor growth

Enabling functional genomics with genome engineering

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