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MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects

HaEun Kim1,2, Benjamin Lebeau1,2,3, David Papadopoli2,4

  • 1Department of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada.

Iscience
|March 4, 2024
PubMed

Insights

Mechanistic target of rapamycin (mTOR) pathway activation or inhibition selectively increases H3K27me3 histone modification. This epigenetic change, mediated by distinct mechanisms, may enhance the anti-proliferative effects of mTOR inhibitors.

Area of Science:

  • Cellular Biology
  • Epigenetics
  • Molecular Biology

Background:

  • Metabolic and epigenetic programs exhibit significant cross-talk.
  • The mechanistic target of rapamycin (mTOR) pathway is a key metabolic regulator.
  • The precise relationship between mTOR signaling and epigenetic modifications is not well understood.

Purpose of the Study:

  • To investigate the impact of mTOR pathway modulation on specific histone modifications.
  • To elucidate the mechanisms underlying changes in histone methylation.
  • To explore the correlation between mTOR-induced epigenetic changes and anti-proliferative effects.

Main Methods:

  • Analysis of histone modifications (H3K27me3, H3K4me3, H3K9me3) in response to mTORC1 activation (TSC2 abrogation) and inhibition.
  • Assessment of EZH2 and EZH1 protein levels.
  • Correlation analysis between H3K27me3 induction and anti-proliferative activity of mTOR inhibitors.

Main Results:

  • mTORC1 activation selectively increased H3K27me3 levels, independent of H3K4me3 and H3K9me3, via increased EZH2.
  • mTOR inhibition also selectively induced H3K27me3 through a mechanism involving reduced EZH2 and increased EZH1.
  • The induction of H3K27me3 by mTOR inhibitors correlated positively with their anti-proliferative effects.

Conclusions:

  • Both activation and inhibition of the mTOR pathway selectively increase H3K27me3 via distinct molecular mechanisms.
  • The selective induction of H3K27me3 may contribute to the anti-proliferative efficacy of mTOR inhibitors.
  • This study reveals a novel link between mTOR signaling and H3K27 trimethylation dynamics.
Keywords:
EpigeneticsMolecular biologyMolecular mechanism of gene regulation

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