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

Abstract

Sin3A/B is a master transcriptional scaffold and corepressor 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, and we 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 alpha-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 alpha, and retinoic acid receptor beta 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 17beta-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.

• Authors: Eduardo F Farias, Kevin Petrie, Boris Leibovitch, Janice Murtagh, Manuel Boix Chornet, Tino Schenk, Arthur Zelent, Samuel Waxman
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 26 Pg. 11811-6 (Jun 29 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 20547842 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• DNA Primers
• Estrogen Receptor alpha
• Receptors, Retinoic Acid
• Repressor Proteins
• SIN3A transcription factor
• SIN3B protein, human
• Sin3b protein, mouse
• retinoic acid receptor beta
• Sin3 Histone Deacetylase and Corepressor Complex

Topics

• Amino Acid Sequence
• Animals
• Base Sequence
• Breast Neoplasms (genetics, metabolism, pathology, therapy)
• Cell Differentiation (genetics)
• Cell Line, Tumor
• Chromatin Assembly and Disassembly
• DNA Primers (genetics)
• Drug Resistance, Neoplasm (genetics)
• Epigenesis, Genetic
• Estrogen Receptor alpha (genetics)
• Female
• Gene Targeting
• Genetic Therapy
• Humans
• Mammary Neoplasms, Experimental (genetics, metabolism, pathology)
• Mice
• Protein Binding
• Protein Structure, Tertiary
• Receptors, Retinoic Acid (genetics)
• Repressor Proteins (antagonists & inhibitors, chemistry, genetics, metabolism)
• Sin3 Histone Deacetylase and Corepressor Complex