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

Ana Tufegdžić Vidaković | Zendy; Oscar M. Rueda | Zendy; Stephin J. Vervoort | Zendy; Ankita Sati Batra | Zendy; Mae A. Goldgraben | Zendy; Santiago UribeLewis | Zendy; Wendy Greenwood | Zendy; Paul J. Coffer | Zendy; Alejandra Bruna | Zendy; Carlos Caldas | Zendy

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

Author(s) -

Ana Tufegdžić Vidaković,

Oscar M. Rueda,

Stephin J. Vervoort,

Ankita Sati Batra,

Mae A. Goldgraben,

Santiago UribeLewis,

Wendy Greenwood,

Paul J. Coffer,

Alejandra Bruna,

Carlos Caldas

Publication year - 2015

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2015.11.040

Subject(s) - epigenome , biology , context (archaeology) , epigenetics , dna methylation , transforming growth factor , transforming growth factor beta , histone , cancer research , regulation of gene expression , effector , cancer , signal transduction , microbiology and biotechnology , gene , genetics , gene expression , paleontology

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.

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