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.
authors.affiliation: Cancer Research UK Cambridge Institute, Department of Oncology, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Tufegdzic Vidakovic
authors.affiliation: Cancer Research UK Cambridge Institute, Department of Oncology, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
authors.forename: Stephin J
authors.initials: SJ
authors.lastname: Vervoort
authors.affiliation: Cancer Research UK Cambridge Institute, Department of Oncology, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Ankita
authors.initials: A
authors.lastname: Sati Batra
authors.affiliation: Cancer Research UK Cambridge Institute, Department of Oncology, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Mae Akilina
authors.initials: MA
authors.lastname: Goldgraben
authors.affiliation: Cancer Research UK Cambridge Institute, Department of Oncology, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Santiago
authors.initials: S
authors.lastname: Uribe-Lewis
authors.affiliation: Cancer Research UK Cambridge Institute, Department of Oncology, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Wendy
authors.initials: W
authors.lastname: Greenwood
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coffer
authors.affiliation: Cancer Research UK Cambridge Institute, Department of Oncology, University of Cambridge, Cambridge CB2 0RE, UK. Electronic address: alejandra.bruna@cruk.cam.ac.uk.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Bruna
authors.affiliation: Cancer Research UK Cambridge Institute, Department of Oncology, University of Cambridge, Cambridge CB2 0RE, UK. Electronic address: carlos.caldas@cruk.cam.ac.uk.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D006801:Humans; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D006657:Histones; C531176:LBH protein, human; D034741:RNA, Small Interfering; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C555441:VGLL3 protein, human; D004247:DNA