YAP-Mediated Recruitment of YY1 and EZH2 Represses Transcription of Key Cell-Cycle Regulators

Abstract

The Hippo pathway regulates cell proliferation and organ size through control of the transcriptional regulators YAP (yesassociated protein) and TAZ. Upon extracellular stimuli such as cell-cell contact, the pathway negatively regulates YAP through cytoplasmic sequestration. Under conditions of low cell density, YAP is nuclear and associates with enhancer regions and gene promoters. YAP is mainly described as a transcriptional activator of genes involved in cell proliferation and survival. Using a genomewide approach, we show here that, in addition to its known function as a transcriptional activator, YAP functions as a transcriptional repressor by interacting with the multifunctional transcription factor Yin Yang 1 (YY1) and Polycomb repressive complex member enhancer of zeste homologue 2 (EZH2). YAP colocalized with YY1 and EZH2 on the genome to transcriptionally repress a broad network of genes mediating a host of cellular functions, including repression of the cell-cycle kinase inhibitor p27, whose role is to functionally promote contact inhibition. This work unveils a broad and underappreciated aspect of YAP nuclear function as a transcriptional repressor and highlights how loss of contact inhibition in cancer is mediated in part through YAP repressive function.Significance: This study provides new insights into YAP as a broad transcriptional repressor of key regulators of the cell cycle, in turn influencing contact inhibition and tumorigenesis.

An Updated Understanding of the Role of YAP in Driving Oncogenic Responses

“…With the concomitant transcriptional activity in favor of the expression of pro-survival genes, YAP is able also to mediate genetic repression of several tumor suppressor genes. This topic has been reported very recently in two seminal papers by Hoxha et al [ 119 ] and Lo Sardo et al [ 120 ]. The first describes how a molecular complex composed by the association of YAP with the factor Yin Yang 1 (YY1), Polycomb repressive complex (PRC2) and the trimethylation of Histone H3 protein (which means genetic silencing) can inhibit CDKN1B gene [ 119 ].…”

“…This topic has been reported very recently in two seminal papers by Hoxha et al [ 119 ] and Lo Sardo et al [ 120 ]. The first describes how a molecular complex composed by the association of YAP with the factor Yin Yang 1 (YY1), Polycomb repressive complex (PRC2) and the trimethylation of Histone H3 protein (which means genetic silencing) can inhibit CDKN1B gene [ 119 ]. Encoding for p27, a protein essential to limit S phase entry of the cell cycle, this clearly sustains cell proliferation.…”

The Hippo pathway: Horizons for innovative treatments of peripheral nerve diseases

“…134,142 Tumors of peripheral nerve, schwannomas and neurofibromas, are benign in the vast majority of clinically symptomatic cases (reviewed in 143 42,145,146 Because the NF2 gene was shown to function upstream of the Hippo pathway, there are numerous evidences that strongly suggest that YAP/TAZ are involved in schwannoma tumorigenesis and NF-2 pathophysiology. 135,[147][148][149][150] A very recent study confirmed this hypothesis by demonstrating that Hippo signaling and YAP/TAZ are required for schwannoma formation. 151 For patients with neurofibromatosis type 1 (NF-1), the incidence of malignancy is significantly greater.…”

The oncogene Mct-1 promotes progression of hepatocellular carcinoma via enhancement of Yap-mediated cell proliferation

“…Notably, Yap exerts a synergistic effect through the recruitment of YY1 and enhancer of zeste homologue 2 (EZH2), which plays a key role in regulating the cyclin-dependent kinase inhibitor p27 and overriding contact inhibition between cells. Further investigations revealed that both YY1 and EZH2 are necessary for Yap-mediated repression of p27 expression 29 , 30 . These results unveiled that Mct-1 has the potential to promote HCC progression via the regulation of p27 expression and impairing the effect of contact inhibition in HCC.…”