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

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

SUBMITTER: Tufegdzic Vidakovic A

PROVIDER: S-EPMC4695334 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Tufegdzic Vidakovic Ana A Rueda Oscar M OM Vervoort Stephin J SJ Sati Batra Ankita A Goldgraben Mae Akilina MA Uribe-Lewis Santiago S Greenwood Wendy W Coffer Paul J PJ Bruna Alejandra A Caldas Carlos C

Cell reports 20151210 11

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 ...[more]

PMID: 26686634

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Project description:Prevailing insulin resistance and the resultant hyperglycemia elicits a compensatory response from pancreatic islet beta cells (β-cells) that involves increases in β-cell function and β-cell mass. However, the sustained metabolic stress eventually leads to β-cell failure characterized by severe β-cell dysfunction and progressive loss of β-cell mass. Whereas, β-cell dysfunction is relatively well understood at the mechanistic level, the avenues leading to loss of β-cell mass are less clear with reduced proliferation, dedifferentiation, and apoptosis all potential mechanisms. Butler and colleagues documented increased β-cell apoptosis in pancreas from lean and obese human Type 2 diabetes (T2D) subjects, with no changes in rates of β-cell replication or neogenesis, strongly suggesting a role for apoptosis in β-cell failure. Here, we describe a permissive role for TGF-β/Smad3 in β-cell apoptosis. Human islets undergoing β-cell apoptosis release increased levels of TGF-β1 ligand and phosphorylation levels of TGF-β's chief transcription factor, Smad3, are increased in human T2D islets suggestive of an autocrine role for TGF-β/Smad3 signaling in β-cell apoptosis. Smad3 phosphorylation is similarly increased in diabetic mouse islets undergoing β-cell apoptosis. In mice, β-cell-specific activation of Smad3 promotes apoptosis and loss of β-cell mass in association with β-cell dysfunction, glucose intolerance, and diabetes. In contrast, inactive Smad3 protects from apoptosis and preserves β-cell mass while improving β-cell function and glucose tolerance. At the molecular level, Smad3 associates with Foxo1 to propagate TGF-β-dependent β-cell apoptosis. Indeed, genetic or pharmacologic inhibition of TGF-β/Smad3 signals or knocking down Foxo1 protects from β-cell apoptosis. These findings reveal the importance of TGF-β/Smad3 in promoting β-cell apoptosis and demonstrate the therapeutic potential of TGF-β/Smad3 antagonism to restore β-cell mass lost in diabetes.

Dataset Information

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

Publications

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

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