Reprogramming epigenetic silencing: artificial transcription factors synergize with chromatin remodeling drugs to reactivate the tumor suppressor mammary serine protease inhibitor.

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TítuloReprogramming epigenetic silencing: artificial transcription factors synergize with chromatin remodeling drugs to reactivate the tumor suppressor mammary serine protease inhibitor.
Publication TypeJournal Article
Year of Publication2008
AutoresBeltran, AS, Sun, X, Lizardi, PM, Blancafort, P
JournalMol Cancer Ther
Volume7
Issue5
Pagination1080-90
Date Published2008 May
ISSN1535-7163
Palabras claveAntineoplastic Combined Chemotherapy Protocols, Azacitidine, Chromatin Assembly and Disassembly, Gene Silencing, Genes, Tumor Suppressor, Humans, Hydroxamic Acids, Models, Biological, Serine Proteinase Inhibitors, Serpins, Transcription Factors, Tumor Cells, Cultured
Abstract

Mammary serine protease inhibitor (maspin) is an important tumor suppressor gene whose expression is associated not only with tumor growth inhibition but also with decreased angiogenesis and metastasis. Maspin expression is down-regulated in metastatic tumors by epigenetic mechanisms, including aberrant promoter hypermethylation. We have constructed artificial transcription factors (ATFs) as novel therapeutic effectors able to bind 18-bp sites in the maspin promoter and reactivate maspin expression in cell lines that harbor an epigenetically silenced promoter. In this article, we have investigated the influence of epigenetic modifications on ATF-mediated regulation of maspin by challenging MDA-MB-231 breast cancer cells, comprising a methylated maspin promoter, with different doses of ATFs and chromatin remodeling drugs: the methyltransferase inhibitor 5-aza-2'-deoxycytidine and the histone deacetylase inhibitor suberoylanilide hydroxamic acid. We found that the ATFs synergized with both inhibitors in reactivating endogenous maspin expression. The strongest synergy was observed with the triple treatment ATF-126 + 5-aza-2'-deoxycytidine + suberoylanilide hydroxamic acid, in which the tumor suppressor was reactivated by 600-fold. Furthermore, this combination inhibited tumor cell proliferation by 95%. Our data suggest that ATFs enhance the efficiency of chromatin remodeling drugs in reactivating silenced tumor suppressors. Our results document the power of a novel therapeutic approach that combines both epigenetic and genetic (sequence-specific ATFs) strategies to reactivate specifically silenced regions of the genome and reprogram cellular phenotypes.

DOI10.1158/1535-7163.MCT-07-0526
Alternate JournalMol. Cancer Ther.
PubMed ID18483297
Grant List1R01CA125273-01 / CA / NCI NIH HHS / United States
R01 CA125273 / CA / NCI NIH HHS / United States
R21 CA116079-01 / CA / NCI NIH HHS / United States