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1000
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Abstract/Summary
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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.
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