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Exploring the Arginine Methylome by Nuclear Magnetic Resonance Spectroscopy
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Exploring the Arginine Methylome by Nuclear Magnetic Resonance Spectroscopy

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Interplay between arginine methylation and ubiquitylation regulates KLF4-mediated genome stability and carcinogenesis

Dong Hu1,2, Mert Gur3, Zhuan Zhou1,2

  • 1Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.

Nature Communications
|October 1, 2015
PubMed

Insights

Protein modification regulates KLF4 stability, impacting cell fate and cancer. Arginine methylation by PRMT5 stabilizes KLF4, promoting cell cycle arrest and suppressing breast tumor growth.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Krüppel-like factor 4 (KLF4) is crucial for cell-fate decisions, including DNA damage response and apoptosis.
  • Protein modifications play a key role in regulating KLF4 function.

Purpose of the Study:

  • To investigate the interplay between protein modifications in regulating KLF4.
  • To elucidate the role of PRMT5-mediated methylation in KLF4 stability and its impact on breast carcinogenesis.

Main Methods:

  • Protein interaction studies
  • Ubiquitylation assays
  • Structure-based modeling and simulations
  • Genotoxicity assays
  • Tumorigenesis models
  • Immunohistochemistry

Main Results:

  • Arginine methylation of KLF4 by PRMT5 inhibits VHL-mediated ubiquitylation, reducing KLF4 turnover and increasing KLF4 protein levels.
  • Elevated KLF4 enhances p21 transcription and represses Bax expression, promoting cell cycle arrest.
  • Disruption of PRMT5-KLF4 methylation abrogates KLF4 accumulation following genotoxic stress, impairing cell cycle arrest.
  • Mutating KLF4 methylation sites suppresses breast tumor initiation and progression.
  • Increased KLF4 and PRMT5 levels are observed in breast cancer tissues.

Conclusions:

  • Aberrant regulation of KLF4 by PRMT5 is critical for genome stability and breast carcinogenesis.
  • Targeting the PRMT5-KLF4 methylation axis represents a potential therapeutic strategy for breast cancer.

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