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

Sany Hoxha, Alyssa Shepard, Scott Troutman, Huitian Diao, Joanne R. Doherty, Michalina Janiszewska, Robert M. Witwicki, Matthew E. Pipkin, William W. Ja, Michael S. Kareta, Joseph L. Kissil

Research output: Contribution to journalArticle

Abstract

The Hippo pathway regulates cell proliferation and organ size through control of the transcriptional regulators YAP (yes-associated 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 genome-wide 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.

Original languageEnglish (US)
Pages (from-to)2512-2522
Number of pages11
JournalCancer Research
Volume80
Issue number12
DOIs
StatePublished - Jun 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Hoxha, S., Shepard, A., Troutman, S., Diao, H., Doherty, J. R., Janiszewska, M., Witwicki, R. M., Pipkin, M. E., Ja, W. W., Kareta, M. S., & Kissil, J. L. (2020). YAP-Mediated Recruitment of YY1 and EZH2 Represses Transcription of Key Cell-Cycle Regulators. Cancer Research, 80(12), 2512-2522. https://doi.org/10.1158/0008-5472.CAN-19-2415