Skip to main content
  • Poster presentation
  • Open access
  • Published:

Gene specific overwriting of epigenetic signatures to modulate the expression of selected tumor-promoting genes in cancer


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 [1]. 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 [2]). 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 [3])] 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.


  1. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations


Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

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).

Download citation

  • Published:

  • DOI: