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

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

doi:10.1016/j.celrep.2015.11.040

Ana Tufegdzic Vidakovic, Stephin J Vervoort + Show 8 more

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https://doi.org/10.1016/j.celrep.2015.11.040

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SummaryThe 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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The effects of transforming growth factor beta (TGF-b) in tissue homeostasis depend heavily on cellular context (Massague, 2012)
We identify transcription factor Limb Bud and Heart Development (LBH) as a prototypical TGF-b target gene regulated by differential DNA methylation and show it is essential for the breast-tumor-initiating cells (BTICs)-promoting activity of TGF-b
To assess the functional implications of epigenome-directed and epigenome-assisted mechanisms, we investigated whether LBH and Vestigial-like family member 3 (VGLL3) are required for the effects of TGF-b on BTICs

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The effects of transforming growth factor beta (TGF-b) in tissue homeostasis depend heavily on cellular context (Massague , 2012). TGF-b has been shown to both induce proliferation and suppress cell growth, stimulate stem cell self-renewal and promote differentiation, and inhibit early and promote late malignant transformation (Gomis et al, 2006; Guasch et al, 2007; Massague , 2008, 2012). TGF-b can either promote or inhibit tumorinitiating cells (breast TICs, or BTICs), which are responsible for cancer initiation, propagation, and metastasis (Bierie and Moses, 2009; Bruna et al, 2012; Mani et al, 2008; Scheel et al, 2011). We have previously shown these opposing effects of TGF-b depend on breast cancer subtype (Bruna et al, 2012). Since no mutations in TGF-b pathway genes have been associated with specific breast cancer subtypes (Cancer Genome Atlas Network, 2012), the underlying mechanism of this dichotomy is unlikely to be genetic

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