SET1A-Mediated Mono-Methylation at K342 Regulates YAP Activation by Blocking Its Nuclear Export and Promotes Tumorigenesis

Cancer Cell. 2018 Jul 9;34(1):103-118.e9. doi: 10.1016/j.ccell.2018.06.002. Epub 2018 Jun 28.


YAP, a key effector of Hippo pathway, is activated by its translocation from cytoplasm to nucleus to regulate gene expression and promote tumorigenesis. Although the mechanism by which YAP is suppressed in cytoplasm has been well-studied, how the activated YAP is sequestered in the nucleus remains unknown. Here, we demonstrate that YAP is a nucleocytoplasmic shuttling protein and its nuclear export is controlled by SET1A-mediated mono-methylation of YAP at K342, which disrupts the binding of YAP to CRM1. YAP mimetic methylation knockin mice are more susceptible to colorectal tumorigenesis. Clinically, YAP K342 methylation is reversely correlated with cancer survival. Collectively, our study identifies SET1A-mediated mono-methylation at K342 as an essential regulatory mechanism for regulating YAP activity and tumorigenesis.

Keywords: SET1A; YAP methylation; nuclear export; tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Active Transport, Cell Nucleus
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Cycle Proteins
  • Cell Nucleus / enzymology*
  • Cell Nucleus / genetics
  • Cell Nucleus / pathology
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Colorectal Neoplasms / enzymology*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • HEK293 Cells
  • HeLa Cells
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Humans
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Lysine
  • Methylation
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Prognosis
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Processing, Post-Translational*
  • Signal Transduction
  • Transcription Factors
  • Tumor Burden
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Phosphoproteins
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Yap1 protein, mouse
  • Histone-Lysine N-Methyltransferase
  • Nsccn1 protein, mouse
  • Setd1A protein, human
  • Lysine