Abstract
An obstacle in the treatment of human diseases such as cancer is the inability to selectively and effectively target historically undruggable targets such as transcription factors. Here, we employ a novel technology using artificial transcription factors (ATFs) to epigenetically target gene expression in cancer cells. We show that site-specific DNA methylation and long-term stable repression of the tumor suppressor Maspin and the oncogene SOX2 can be achieved in breast cancer cells via zinc-finger ATFs targeting DNA methyltransferase 3a (DNMT3a) to the promoters of these genes. Using this approach, we show Maspin and SOX2 downregulation is more significant as compared with transient knockdown, which is also accompanied by stable phenotypic reprogramming of the cancer cell. These findings indicate that multimodular Zinc Finger Proteins linked to epigenetic editing domains can be used as novel cell resources to selectively and heritably alter gene expression patterns to stably reprogram cell fate.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Base Sequence
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Cell Line, Tumor
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Cell Proliferation
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Cell Survival
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DNA (Cytosine-5-)-Methyltransferases / genetics
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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DNA Methylation*
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DNA Methyltransferase 3A
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Epigenesis, Genetic*
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Female
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Gene Expression Regulation, Neoplastic*
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Gene Knockdown Techniques
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Genes, Neoplasm
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Genetic Vectors / genetics
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Genetic Vectors / metabolism
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Humans
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Lentivirus / genetics
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Lentivirus / metabolism
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Promoter Regions, Genetic
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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SOXB1 Transcription Factors / genetics
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SOXB1 Transcription Factors / metabolism
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Serpins / genetics
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Serpins / metabolism
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Transfection
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Zinc Fingers
Substances
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DNMT3A protein, human
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RNA, Small Interfering
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SERPIN-B5
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SOX2 protein, human
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SOXB1 Transcription Factors
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Serpins
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DNA (Cytosine-5-)-Methyltransferases
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DNA Methyltransferase 3A