TRPS1 shapes YAP/TEAD-dependent transcription in breast cancer cells
journal contributionposted on 2020-07-15, 11:11 authored by Dana Elster, Marie Tollot, Karin Schlegelmilch, Alessandro Ori, Andreas Rosenwald, Erik Sahai, Björn von Eyss
Yes-associated protein (YAP), the downstream transducer of the Hippo pathway, is a key regulator of organ size, differentiation and tumorigenesis. To uncover Hippo-independent YAP regulators, we performed a genome-wide CRISPR screen that identifies the transcriptional repressor protein Trichorhinophalangeal Syndrome 1 (TRPS1) as a potent repressor of YAP-dependent transactivation. We show that TRPS1 globally regulates YAP-dependent transcription by binding to a large set of joint genomic sites, mainly enhancers. TRPS1 represses YAP-dependent function by recruiting a spectrum of corepressor complexes to joint sites. Loss of TRPS1 leads to activation of enhancers due to increased H3K27 acetylation and an altered promoter-enhancer interaction landscape. TRPS1 is commonly amplified in breast cancer, which suggests that restrained YAP activity favours tumour growth. High TRPS1 activity is associated with decreased YAP activity and leads to decreased frequency of tumour-infiltrating immune cells. Our study uncovers TRPS1 as an epigenetic regulator of YAP activity in breast cancer.
AcetylationAnimalsBinding SitesBreast NeoplasmsCRISPR-Cas SystemsCell Line, TumorChromatinDNA-Binding ProteinsEnhancer Elements, GeneticEpigenesis, GeneticFemaleGene Expression Regulation, NeoplasticGenomicsHEK293 CellsHumansMCF-7 CellsMiceMice, Inbred BALB CNeoplasm TransplantationPromoter Regions, GeneticRNA, Small InterferingTissue Array AnalysisTranscription FactorsTranscriptional ActivationSahai FC001144