GSE125594
A non-canonical role of YAP/TEAD is required for activation of estrogen-regulated enhancers in breast cancer [ChIP-seq]
Estrogen and estrogen receptor alpha (ERa) signaling plays an essential role in ERa-positive breast cancer. ERa mainly occupies on distal enhancers within genome and requires the cooperation of additional co-factors to tune the enhancer activity. Through in vivo proximity-dependent labeling technique BioID, we identified YAP1 and TEAD4 protein as novel co-regulators of ERa. YAP and TEAD are nuclear effectors of the Hippo pathway regulating cell proliferation, organ size and tumorigenesis. Their non-canonical function as transcriptional co-regulators for other signals have been reported but remains under investigated. Our ChIP-seq data in both MCF7 and T47D breast cancer cell lines indicated that YAP1 and TEAD4 co-bind to the strongest estrogen-responsive ERa-bound enhancers, and their bindings are augmented upon E2 stimulation. Knockdown of YAP1 or TEAD4 showed a global effect on the induction of E2/ERa target genes as examined by RNA-seq, also on E2-induced oncogenic growth of ER-positive breast cancer cells. We used Global Run-on sequencing (GRO-seq) assays to test the expression of enhancer non-coding RNAs (eRNAs), which are sensitive markers for estrogen-induced enhancer activation. Our results supported our hypothesis that the recruitment YAP/TEAD to ERa-bound enhancers is required for enhancer activation. Further studies revealed that the binding of YAP1 on ERa enhancers is a prerequisite for the recruitment of the enhancer activation machinery component MED1. These findings indicate that ERa collaborates with YAP1 and TEAD4 to activate or maintain its enhancer activity. Our data reveals a non-canonical function of YAP1 and TEAD4, which is independent of their canonical target genes, in regulating cancer growth, highlighting the potential of YAP1 and TEAD4 as actionable drug targets for ERa-positive breast cancer. Overall design: Chromatin immunoprecipitation (ChIP) assay followed by high-throughput sequencing (ChIP-seq).