TY - JOUR
T1 - Context-Specific Effects of TGF-β/SMAD3 in Cancer Are Modulated by the Epigenome
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.
UR - http://www.scopus.com/inward/record.url?scp=84952871496&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2015.11.040
DO - 10.1016/j.celrep.2015.11.040
M3 - Article
C2 - 26686634
AN - SCOPUS:84952871496
SN - 2211-1247
VL - 13
SP - 2480
EP - 2490
JO - Cell Reports [E]
JF - Cell Reports [E]
IS - 11
ER -