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Updated: Jul 19, 2025

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TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential

Jing He1, Mingen Lin1, Xinchao Zhang1

  • 1MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

Cell Discovery
|August 7, 2023
PubMed

Insights

TET2 (ten-eleven translocation 2) suppresses cell growth by inhibiting mTORC1 signaling. TET2 deficiency in tumors increases sensitivity to mTORC1 inhibitors, suggesting a potential therapeutic strategy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Tumorigenesis involves complex signaling pathways regulating cell growth and proliferation.
  • TET2 is a DNA dioxygenase known to modify DNA methylation but its role in cell growth regulation is unclear.

Purpose of the Study:

  • To investigate the function of TET2 in regulating cell growth.
  • To elucidate the molecular mechanisms by which TET2 influences cell growth and signaling pathways.

Main Methods:

  • Investigated TET2's role in cell growth and mTORC1 signaling.
  • Examined TET2's mechanism involving mRNA oxidation, protein binding, and mRNA decay.
  • Assessed urea cycle enzyme mRNA levels and arginine production.
  • Evaluated sensitivity of TET2-deficient tumor cells to mTORC1 inhibition.

Main Results:

  • TET2 suppresses mTORC1 signaling, thereby inhibiting cell growth and promoting autophagy.
  • TET2 acts as a 5-methylcytosine (5mC) "eraser" through mRNA oxidation, disrupting YBX1-HuR binding and promoting urea cycle enzyme mRNA decay.
  • This process negatively regulates the urea cycle and arginine production, leading to mTORC1 suppression.
  • TET2-deficient tumor cells exhibit increased sensitivity to mTORC1 inhibition.

Conclusions:

  • TET2 plays a novel role in suppressing mTORC1 signaling and inhibiting cell growth.
  • TET2-mediated mRNA oxidation links DNA modification to cell metabolism and growth control.
  • mTORC1 inhibition presents a potential therapeutic strategy for TET2-deficient tumors.

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