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Analysis of mRNA Nuclear Export Kinetics in Mammalian Cells by Microinjection
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SET1A-Mediated Mono-Methylation at K342 Regulates YAP Activation by Blocking Its Nuclear Export and Promotes

Lan Fang1, Hongqi Teng1, Yilin Wang2

  • 1Shanghai Tenth People's Hospital of Tongji University, School of Medicine and School of Life Science and Technology, Tongji University, Shanghai 200072, China.

Cancer Cell
|July 17, 2018
PubMed

Insights

The Yes-associated protein (YAP) nuclear export is regulated by SET1A-mediated mono-methylation at K342, disrupting CRM1 binding. This finding reveals a novel mechanism controlling YAP activity and tumorigenesis.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Epigenetics

Background:

  • The Yes-associated protein (YAP) is a crucial regulator of gene expression and a key effector of the Hippo pathway.
  • YAP activation involves translocation from the cytoplasm to the nucleus, promoting tumorigenesis.
  • While YAP's cytoplasmic suppression is understood, its nuclear sequestration mechanisms remain unclear.

Purpose of the Study:

  • To investigate the regulatory mechanisms controlling activated YAP's nuclear localization.
  • To identify the factors and modifications responsible for YAP nuclear export control.
  • To explore the role of YAP regulation in colorectal tumorigenesis and cancer survival.

Main Methods:

  • Investigated YAP as a nucleocytoplasmic shuttling protein.
  • Identified SET1A-mediated mono-methylation at K342 as a regulator of YAP nuclear export.
  • Analyzed the disruption of YAP-CRM1 binding by K342 methylation.
  • Utilized YAP mimetic methylation knockin mice models.
  • Correlated YAP K342 methylation levels with clinical cancer survival data.

Main Results:

  • YAP undergoes nucleocytoplasmic shuttling, with nuclear export controlled by SET1A-mediated mono-methylation at K342.
  • This specific methylation disrupts the interaction between YAP and CRM1, a key export receptor.
  • YAP mimetic methylation knockin mice exhibited increased susceptibility to colorectal tumorigenesis.
  • Clinical analysis revealed a reverse correlation between YAP K342 methylation and patient survival in cancer.

Conclusions:

  • SET1A-mediated mono-methylation at K342 is a critical regulatory mechanism for YAP nuclear export.
  • This epigenetic modification plays a significant role in controlling YAP activity and its contribution to tumorigenesis.
  • YAP K342 methylation serves as a potential prognostic biomarker for cancer survival.
Keywords:
SET1AYAP methylationnuclear exporttumorigenesis

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