Interference with Sin3 function induces epigenetic reprogramming and differentiation in breast cancer cells

Eduardo F. Farias, Kevin Petrie, Boris Leibovitch, Janice Murtagh, Manuel Boix Chornet, Tino Schenk, Arthur Zelent, Samuel Waxmana

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Sin3A/B is amaster transcriptional scaffold andcorepressor that plays an essential role in the regulation of gene transcription and maintenance of chromatin structure, and its inappropriate recruitment has been associated with aberrant gene silencing in cancer. Sin3A/B are highly related, large, multidomian proteins that interact with a wide variety of transcription factors and corepressor components, andwe examined whether disruption of the function of a specific domain could lead to epigenetic reprogramming and derepression of specific subsets of genes. To this end, we selected the Sin3A/B-paired amphipathic α-helices (PAH2) domain based on its established role in mediating the effects of a relatively small number of transcription factors containing a PAH2-binding motif known as the Sin3 interaction domain (SID). Here, we show that in both human and mouse breast cancer cells, the targeted disruption of Sin3 function by introduction of a SID decoy that interferes with PAH2 binding to SID-containing partner proteins reverted the silencing of genes involved in cell growth and differentiation. In particular, the SID decoy led to epigenetic reprogramming and reexpression of the important breast cancer-associated silenced genes encoding E-cadherin, estrogen receptor α, and retinoic acid receptor β and impaired tumor growth in vivo. Interestingly, the SID decoy was effective in the triple-negative M.D. Anderson-Metastatic Breast-231 (MDA-MB-231) breast cancer cell line, restoring sensitivity to 17β-estradiol, tamoxifen, and retinoids. Therefore, the development of small molecules that can block interactions between PAH2 and SID-containing proteins offers a targeted epigenetic approach for treating this type of breast cancer that may also have wider therapeutic implications.

Original languageEnglish (US)
Pages (from-to)11811-11816
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number26
DOIs
StatePublished - Jun 29 2010

Keywords

  • E-cadherin
  • Estrogen receptor
  • Sin3 interaction domain
  • Triple-negative

ASJC Scopus subject areas

  • General

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