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

Ana Tufegdzic Vidakovic; Oscar M. Rueda; Stephin J. Vervoort; Ankita Sati Batra; Mae Akilina Goldgraben; Santiago Uribe-Lewis; Wendy Greenwood; Paul J. Coffer; Alejandra Bruna; Carlos Caldas

doi:10.1016/j.celrep.2015.11.040

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

Ana Tufegdzic Vidakovic
, Oscar M. Rueda
, Stephin J. Vervoort
, Ankita Sati Batra
, Mae Akilina Goldgraben
, Santiago Uribe-Lewis
, Wendy Greenwood
, Paul J. Coffer
, Alejandra Bruna^*
, Carlos Caldas

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

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.

Original language	English
Pages (from-to)	2480-2490
Number of pages	11
Journal	Cell Reports
Volume	13
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2015.11.040
State	Published - 22 Dec 2015
Externally published	Yes

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Publisher Copyright:
© 2015 The Authors.

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10.1016/j.celrep.2015.11.040

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

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.",

author = "\{Tufegdzic Vidakovic\}, Ana and Rueda, \{Oscar M.\} and Vervoort, \{Stephin J.\} and \{Sati Batra\}, Ankita and Goldgraben, \{Mae Akilina\} and Santiago Uribe-Lewis and Wendy Greenwood and Coffer, \{Paul J.\} and Alejandra Bruna and Carlos Caldas",

note = "Publisher Copyright: {\textcopyright} 2015 The Authors.",

year = "2015",

month = dec,

day = "22",

doi = "10.1016/j.celrep.2015.11.040",

language = "אנגלית",

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AU - Tufegdzic Vidakovic, Ana

AU - Rueda, Oscar M.

AU - Vervoort, Stephin J.

AU - Sati Batra, Ankita

AU - Goldgraben, Mae Akilina

AU - Uribe-Lewis, Santiago

AU - Greenwood, Wendy

AU - Coffer, Paul J.

AU - Bruna, Alejandra

AU - Caldas, Carlos

PY - 2015/12/22

Y1 - 2015/12/22

N2 - 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.

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

Abstract

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