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Context-Specific Effects of TGF-β/SMAD3 in Cancer Are Modulated by the Epigenome.


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Authors

Tufegdzic Vidakovic, Ana 
Rueda, Oscar M 
Vervoort, Stephin J 
Sati Batra, Ankita 
Goldgraben, Mae Akilina 

Abstract

The transforming growth factor beta (TGF-β) signaling pathway exerts opposing effects on cancer cells, acting as either a tumor promoter or a tumor suppressor. Here, we show that these opposing effects are a result of the synergy between SMAD3, a downstream effector of TGF-β signaling, and the distinct epigenomes of breast-tumor-initiating cells (BTICs). These effects of TGF-β are associated with distinct gene expression programs, but genomic SMAD3 binding patterns are highly similar in the BTIC-promoting and BTIC-suppressing contexts. Our data show cell-type-specific patterns of DNA and histone modifications provide a modulatory layer by determining accessibility of genes to regulation by TGF-β/SMAD3. LBH, one such context-specific target gene, is regulated according to its DNA methylation status and is crucial for TGF-β-dependent promotion of BTICs. Overall, these results reveal that the epigenome plays a central and previously overlooked role in shaping the context-specific effects of TGF-β in cancer.

Description

Keywords

Binding Sites, Cell Line, Tumor, DNA, DNA Methylation, Epigenesis, Genetic, Histones, Humans, Neoplastic Stem Cells, Promoter Regions, Genetic, Protein Binding, RNA Interference, RNA, Small Interfering, Signal Transduction, Smad2 Protein, Smad3 Protein, Trans-Activators, Transcription Factors, Transforming Growth Factor beta

Journal Title

Cell Rep

Conference Name

Journal ISSN

2211-1247
2211-1247

Volume Title

13

Publisher

Elsevier BV
Sponsorship
Cancer Research UK (CB4140)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (60098573)
Cancer Research UK (unknown)
Cancer Research UK (16942)
S.J.V. was supported by a grant from the Dutch Cancer Foundation (KWF).