BRD2 Promotes TGF-β Transcriptional Responses Through Cooperation With Smad3

The transforming growth factor-β(TGF-β)family is a multifunctional cytokine family with a wide range of cell biological functions,not only regulating cell growth,proliferation,differentiation,migration and apoptosis,but also participating in early embryonic development,tissue and organ formation and immunity.Deregulation of TGF-β signaling leads to a variety of diseases,such as tumorigenesis,tissue fibrosis and dysplasia.Activation of TGF-β signaling pathway is usually initiated by the binding of TGF-β ligands to serine/threonine kinase-type receptors on the cell membrane.After the receptors are activated by ligands,the receptors will phosphorylate intracellular Smad2 and Smad3.Subsequently,two phosphorylated R-Smads form a heterotrimeric complex with Smad4.The resulting trimeric complex is rapidly translocated into the nucleus where it elicits transcriptional responses via binding with Smad-binding-element to regulate the expression of specific target genes.This process requires the participation of transcription factors or accessory proteins to provide affinity and selectivity for Smads-DNA binding.Therefore,these transcription factors or cofactors can provide the specificity and selectivity of TGF-βsignaling from different levels,including the selection of target genes and the responsive modes of target genes.That is important for selection of cell fates.Here,we found a novel protein BRD2 that regulates the transcriptional functions of TGF-β signaling pathway by screening.BRD2 belongs to the bromodomain and extraterminal domain(BET)family,which is a class of proteins with bromodomains that can specifically recognize acetylated histones to regulate transcription.In this study,we found that BRD2 can regulate TGF-β signaling pathway through cooperation with Smad3.We found that BRD2 directly interacts with Smad3.However,BRD2 has no function on the activation of Smad2/3 and the formation of Smads complex.Furthermore,BRD2 forms a TGF-β inducible complex with the MH1 domain of Smad3 through its C-terminal region(amino acids 715-801).In addition,BRD2 simultaneously binds to acetylated histones(H4K12ac/H3K9ac)to promote Smad3-chromatin association,thereby enhancing the transcriptional activity of Smad complex.In addition,BRD2 enhances transcriptional regulation of TGF-βand TGF-β-induced proliferation inhibition and tumor suppressive responses.In summary,we found a novel regulator BRD2,which promotes TGF-βsignaling and inhibits tumor growth of TGF-β-related cancers through cooperation with Smad3.Our finding provides a theoretical basis for further understanding the regulation of TGF-β signaling and the functions of BRD2 in cancer therapy.