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Mammalian target of rapamycin complex 2 (mTORC2) controls glycolytic gene expression by regulating Histone H3 Lysine

Raghavendra Vadla1,2, Devyani Haldar1

  • 1a Centre for DNA Fingerprinting and Diagnostics , Survey Nos. 728, 729, 730 & 734, Opposite Uppal Water Tank, Beside BSNL T E Building, Uppal, Hyderabad 500039 , Ranga Reddy District , India.

Cell Cycle (Georgetown, Tex.)
|November 17, 2017
PubMed

Insights

Mammalian target of rapamycin complex 2 (mTORC2) promotes histone H3 lysine 56 acetylation (H3K56Ac) in glioma. This epigenetic modification regulates glycolytic gene expression, suggesting a novel mechanism for cancer metabolic reprogramming.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Metabolic reprogramming is crucial for cancer development.
  • The mammalian target of rapamycin complex 2 (mTORC2) influences cell growth and metabolism.
  • The role of mTORC2 in epigenetic regulation of gene expression in glioma remains unclear.

Purpose of the Study:

  • To investigate the role of mTORC2 in epigenetic modifications in glioma.
  • To determine if mTORC2 regulates histone H3 lysine 56 acetylation (H3K56Ac).
  • To elucidate the mechanism by which mTORC2 influences gene expression and metabolic reprogramming in glioma.

Main Methods:

  • Knockdown of mTORC2 and mTORC1 to assess effects on H3K56Ac levels.
  • Investigated the involvement of tuberous sclerosis complex 1/2 (TSC1/2) and sirtuin6 (SIRT6) in the mTORC2-mediated H3K56Ac pathway.
  • Utilized a glioma cell model (U87EGFRvIII) to study mTORC2's role in H3K56Ac.
  • Analyzed H3K56Ac levels at the promoters of glycolytic genes.

Main Results:

  • mTORC2 knockdown, but not mTORC1 knockdown, led to decreased global H3K56Ac levels.
  • mTORC2 promotes H3K56Ac via a TSC1/2-mediated pathway.
  • SIRT6 knockdown prevented H3K56 deacetylation in mTORC2-depleted cells.
  • mTORC2 was confirmed to promote H3K56Ac in glioma cells.
  • mTORC2 regulates glycolytic gene expression by modulating H3K56Ac at gene promoters.
  • mTORC2 depletion increased SIRT6 recruitment to these promoters.

Conclusions:

  • mTORC2 signaling positively regulates H3K56Ac in glioma.
  • mTORC2-mediated H3K56Ac is a key mechanism in glioma metabolic reprogramming.
  • This study identifies a novel link between mTORC2, epigenetic modification, and cancer metabolism.
Keywords:
Cancer cellsEGFRGliomaHistone acetylationHistone deacetylasesSIRT6TSC1/2growth factorsmTORmetabolic reprogrammingmetabolismsignal transduction

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