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

被引：27

作者：

Vidakovic, Ana Tufegdzic ^{[1
]}

Rueda, Oscar M. ^{[1
]}

Vervoort, Stephin J. ^{[2
]}

Batra, Ankita Sati ^{[1
]}

Goldgraben, Mae Akilina ^{[1
]}

Uribe-Lewis, Santiago ^{[1
]}

Greenwood, Wendy ^{[1
]}

Coffer, Paul J. ^{[2
]}

Bruna, Alejandra ^{[1
]}

Caldas, Carlos ^{[1
]}

机构：

[1] Univ Cambridge, Dept Oncol, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England

[2] Univ Med Ctr Utrecht, Dept Cell Biol, Ctr Mol Med, NL-3584 CX Utrecht, Netherlands

来源：

CELL REPORTS | 2015年 / 13卷 / 11期

关键词：

TGF-BETA; BREAST-CANCER; FUNCTIONAL-CHARACTERIZATION; SMAD; DNA; METHYLATION; CELLS; PROMOTER; BINDING; IDENTIFICATION;

D O I：

10.1016/j.celrep.2015.11.040

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The transforming growth factor beta (TGF-beta) 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-beta signaling, and the distinct epigenomes of breast-tumor-initiating cells (BTICs). These effects of TGF-beta 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-beta/SMAD3. LBH, one such context-specific target gene, is regulated according to its DNA methylation status and is crucial for TGF-beta-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-beta in cancer.

引用

页码：2480 / 2490

页数：11

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