Pluto Bioinformatics

GSE125606: A non-canonical role ofYAP/TEADis required for activation ofestrogen-regulated enhancers in breast cancer [RNA-seq]

Bulk RNA sequencing

Estrogen and estrogen receptor alpha (ER) signaling plays an essential role in ER-positive breast cancer. ER 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 ER. 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 ER-bound enhancers, and their bindings are augmented upon E2 stimulation. Knockdown of YAP1 or TEAD4 showed a global effect on the induction of E2/ER 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 ER-bound enhancers is required for enhancer activation. Further studies revealed that the binding of YAP1 on ER enhancers is a prerequisite for the recruitment of the enhancer activation machinery component MED1. These findings indicate that ER 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 ER-positive breast cancer. SOURCE: Zhijie,Jason,Liu (liuz7@uthscsa.edu) - Liu lab Universality of Texas Health Science Center at San Antonio