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Regulation of cholesterol biosynthesis by CTCF and H3K27 methylation is critical for cell migration

Lukasz Stanislaw Kaczmarczyk1, Dagmawit Babele1, Nehora Levi1

  • 1Department of Molecular Biology, Faculty of Life Sciences and Ariel Center for Applied Cancer Research, Ariel University, Ariel 40700, Israel.

European Journal of Cell Biology
|September 4, 2024
PubMed

Insights

CTCF (CCCTC-binding factor) loss impairs melanoma cell migration by increasing cholesterol synthesis. Suppressing cholesterol restores migration, revealing CTCF

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • CTCF (CCCTC-binding factor) is crucial for 3D chromatin organization and gene regulation.
  • Its role in cancer cell migration is not fully understood.
  • CTCF influences cell migration through mechanisms requiring elucidation.

Purpose of the Study:

  • To investigate the mechanism by which CTCF affects cancer cell migration.
  • To identify the molecular pathways regulated by CTCF in melanoma cells.
  • To understand CTCF's role in cholesterol biosynthesis and its impact on cell motility.

Main Methods:

  • Utilized mouse melanoma cells with partial loss of function (pLoF) in CTCF.
  • Assessed cell migration rates and migrasome formation.
  • Quantified cholesterol biosynthesis enzyme expression and cellular cholesterol levels.
  • Analyzed CTCF binding, PRC2 recruitment, and H3K27me3 deposition at the Hmgcs1 promoter.

Main Results:

  • CTCF pLoF significantly inhibited melanoma cell migration.
  • CTCF loss led to increased expression of cholesterol biosynthesis enzymes and elevated cellular cholesterol.
  • Reduced migrasome formation was observed in CTCF pLoF cells, indicating altered membrane dynamics.
  • Inhibiting cholesterol synthesis rescued migration rate and migrasome formation in CTCF pLoF cells.
  • CTCF was found to prevent promoter looping and suppress Hmgcs1 transcription via PRC2 and H3K27me3, thereby limiting SREBP2 binding.

Conclusions:

  • CTCF suppresses cholesterol biosynthesis to support melanoma cell migration.
  • CTCF regulates Hmgcs1 transcription through epigenetic mechanisms involving PRC2 and H3K27me3.
  • CTCF acts as a novel regulator of cholesterol biosynthesis, with implications for cholesterol-associated diseases.
Keywords:
Cell migrationCholesterolChromatinFatostatinMigrasomeSREBPTranscription regulation

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