A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells

Nat Commun. 2017 Mar 23;8:14744. doi: 10.1038/ncomms14744.

Abstract

Individual human epidermal cells differ in their self-renewal ability. To uncover the molecular basis for this heterogeneity, we performed genome-wide pooled RNA interference screens and identified genes conferring a clonal growth advantage on normal and neoplastic (cutaneous squamous cell carcinoma, cSCC) human epidermal cells. The Hippo effector YAP was amongst the top positive growth regulators in both screens. By integrating the Hippo network interactome with our data sets, we identify WW-binding protein 2 (WBP2) as an important co-factor of YAP that enhances YAP/TEAD-mediated gene transcription. YAP and WPB2 are upregulated in actively proliferating cells of mouse and human epidermis and cSCC, and downregulated during terminal differentiation. WBP2 deletion in mouse skin results in reduced proliferation in neonatal and wounded adult epidermis. In reconstituted epidermis YAP/WBP2 activity is controlled by intercellular adhesion rather than canonical Hippo signalling. We propose that defective intercellular adhesion contributes to uncontrolled cSCC growth by preventing inhibition of YAP/WBP2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation / genetics*
  • Cells, Cultured
  • Epidermal Cells
  • Female
  • Gene Expression Regulation
  • Humans
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Knockout
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Stem Cells / cytology
  • Stem Cells / metabolism*
  • Trans-Activators
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Trans-Activators
  • Transcription Factors
  • WBP2 protein, human
  • YY1AP1 protein, human