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Gene specific overwriting of epigenetic signatures to modulate the expression of selected tumor-promoting genes in cancer
Epigenetics & Chromatin volume 6, Article number: P15 (2013)
Epidermal Growth Factor Receptor-2 (HER-2) and Estrogen receptor-alpha (ER-α) have been found to be dysregulated in several types of cancer. Their dysregulation is associated with aberrant epigenetic modifications. Additionally, expression of ER-α and HER-2 is inversely correlated; their crosstalk has been shown to be involved in endocrine therapy resistance mechanisms . Therapies targeting either receptor result in cell proliferation inhibition for some cancer types; the anti-cancer effect might be further optimized to be more efficient and applicable for more cancer types by co-targeting the genes at the DNA level. As epigenetic modifications provide a way to modify expression of genes in a sustained manner we aim to downregulate HER-2 and ER-α by inducing epigenetic silencing marks specifically onto their promoters (Epigenetic Editing ). We also aim to discover the possible crosstalk of ER-a with HER-2 and other important genes in cancer.
Methods and materials
Towards downregulation of HER-2 and ER-α, expression and epigenetic modification status of promoter of these genes were assessed in a panel of cancer cell lines (bisulfite sequencing and ChIP). Designed zinc finger proteins (ZFPs) targeting genes promoters were fused to a transcription repressor domain [SKD, histone methyltransferases (G9a, SUV39H1), or a DNA methyltransferase domain (C141S )] and expressed in cancer cells through viral transduction.
HER2-ZFP fused to G9a or SUV39H1 induced the intended silencing histone methylation marks (H3K9me2, H3K9me3) on the HER-2 promoter. Up to 4-fold induced H3K9me2 mark was associated with up to 54 ± 2.9% downregulation of HER-2 expression (P<0.0001). Of note, downregulation of HER-2 by induced H3K9 methylation mark was associated with inhibition of cell proliferation and clonogenicity. Additionally, up to 50% downregulation of ER-α was obtained by a ZFP specif c to ER-α fused to SKD, G9a, and C141S.
These results show that targeted induction of epigenetic marks is instructive in downregulation of HER-2 and ER-α expression. We conclude that Epigenetic Editing might provide a novel and synergistic approach to modulate (onco)genes. In addition, investigation of ER-α crosstalk with HER-2 and other genes might be promising to better interfere with pathways involved in cancer.
Arpino G, Wiechmann L, Osborne CK, Schif R: Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev. 2008, 29 (2): 217-233.
de Groote ML, Verschure PJ, Rots MG: Epigenetic editing: Targeted rewriting of epigenetic marks to Modulate Expression of selected target genes. Nucleic Acids Res. 2012, 40 (21): 10596-10613. 10.1093/nar/gks863.
van der Gun BT, Maluszynska-Hofman M, Kiss A, Arendzen AJ, Ruiters MH, McLaughlin PM, Weinhold E, Rots MG: Targeted DNA methylation by a DNA methyltransferase coupled to a triple helix forming oligonucleotide to down-regulate the epithelial cell adhesion molecule. Bioconjug Chem. 2010, 21 (7): 1239-1245. 10.1021/bc1000388.
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Cite this article
Falahi, F., Huisman, C., Diaz, E.G. et al. Gene specific overwriting of epigenetic signatures to modulate the expression of selected tumor-promoting genes in cancer. Epigenetics & Chromatin 6 (Suppl 1), P15 (2013). https://doi.org/10.1186/1756-8935-6-S1-P15
- Epigenetic Modification
- H3K9 Methylation
- Methylation Mark
- Target Gene Promoter
- Synergistic Approach