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TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential.
- Source :
- Cell Discovery; 8/8/2023, Vol. 9 Issue 1, p1-15, 15p
- Publication Year :
- 2023
-
Abstract
- Tumor development, involving both cell growth (mass accumulation) and cell proliferation, is a complex process governed by the interplay of multiple signaling pathways. TET2 mainly functions as a DNA dioxygenase, which modulates gene expression and biological functions via oxidation of 5mC in DNA, yet whether it plays a role in regulating cell growth remains unknown. Here we show that TET2 suppresses mTORC1 signaling, a major growth controller, to inhibit cell growth and promote autophagy. Mechanistically, TET2 functions as a 5mC "eraser" by mRNA oxidation, abolishes YBX1–HuR binding and promotes decay of urea cycle enzyme mRNAs, thus negatively regulating urea cycle and arginine production, which suppresses mTORC1 signaling. Therefore, TET2-deficient tumor cells are more sensitive to mTORC1 inhibition. Our results uncover a novel function for TET2 in suppressing mTORC1 signaling and inhibiting cell growth, linking TET2-mediated mRNA oxidation to cell metabolism and cell growth control. These findings demonstrate the potential of mTORC1 inhibition as a possible treatment for TET2-deficient tumors. [ABSTRACT FROM AUTHOR]
- Subjects :
- CELL growth
UREA
DIOXYGENASES
CELL metabolism
CELL proliferation
GENE expression
Subjects
Details
- Language :
- English
- ISSN :
- 20565968
- Volume :
- 9
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Cell Discovery
- Publication Type :
- Academic Journal
- Accession number :
- 169810089
- Full Text :
- https://doi.org/10.1038/s41421-023-00567-7