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Updated: Nov 14, 2025

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The activity of the EMT suppressor GRHL2 is regulated by SUMOylation

Sonja Santjer1, Yang Xu1, Sabine Riethdorf1

  • 1Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The Journal of Biological Chemistry
|September 1, 2025
PubMed

Insights

The developmental transcription factor grainyhead-like 2 (GRHL2) is regulated by SUMOylation and phosphorylation, impacting its activity in cancer. Misfolding and nuclear aggresome formation also repress GRHL2, highlighting complex control mechanisms in carcinogenesis.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • The transcription factor grainyhead-like 2 (GRHL2) has dual roles in cancer, acting as both a tumor suppressor and promoter.
  • Mechanisms controlling GRHL2 expression and activity in cancer remain largely unknown.

Purpose of the Study:

  • To elucidate the regulatory mechanisms governing GRHL2 activity in cancer cells.
  • To identify post-translational modifications and structural properties influencing GRHL2 function.

Main Methods:

  • Yeast two-hybrid screening to identify GRHL2 interactors.
  • SUMOylation and phosphorylation site mapping (Lysine 159, Threonine 164).
  • Structural analysis of GRHL2, including propensity for misfolding and aggresome formation.
  • Immunohistochemical analysis of GRHL2 in breast cancer tissues.

Main Results:

  • Identified SUMOylation machinery components as GRHL2 interactors.
  • Discovered a key SUMOylation site (Lysine 159) that enhances GRHL2 transcriptional activity.
  • Found that p38α/β MAPKs phosphorylation (Threonine 164) and PIAS E3 ligase interaction stimulate GRHL2 SUMOylation.
  • Characterized GRHL2 as an intrinsically disordered protein prone to nuclear misfolding and aggresome formation, leading to transcriptional repression.
  • Demonstrated the significance of GRHL2 subnuclear localization in breast carcinogenesis.

Conclusions:

  • GRHL2 activity is intricately regulated by SUMOylation and phosphorylation, with specific sites modulating its function.
  • GRHL2's intrinsically disordered nature contributes to its regulation through misfolding and aggresome formation.
  • Subnuclear compartmentalization of GRHL2 plays a critical role in breast cancer development.
Keywords:
Epithelial-mesenchymal transition (EMT)SUMOylationbreast cancerinvasionmetastasisoncogeneposttranslational modification (PTM)transcription factor

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