TY - JOUR
T1 - L-2hydroxyglutaric acid rewires amino acid metabolism in colorectal cancer via the mTOR-ATF4 axis
AU - Tabata, Sho
AU - Kojima, Yasushi
AU - Sakamoto, Takeharu
AU - Igarashi, Kaori
AU - Umetsu, Ko
AU - Ishikawa, Takamasa
AU - Hirayama, Akiyoshi
AU - Kajino-Sakamoto, Rie
AU - Sakamoto, Naoya
AU - Yasumoto, Ken ichi
AU - Okano, Keiichi
AU - Suzuki, Yasuyuki
AU - Yachida, Shinichi
AU - Aoki, Masahiro
AU - Soga, Tomoyoshi
N1 - Funding Information:
We thank M. Oishi, A. Ueno, and S. Sato for their technical assistance, and Drs. T. Nishihara and M. Sugimoto for their helpful discussions and insights. This study was supported by the Japan Society for the Promotion of Science KAKENHI (17KK0199, ST; 22K07150, ST), CREST from Japan Science and Technology Agency (JPMJCR2123, T Soga), AMED-CREST from the Japan Agency for Medical Research and Development (JP18gm0710003, SY, MA, and T Soga; JP21zf0127001, T Soga), and research funds from the Yamagata Prefecture Government, Japan, and City of Tsuruoka, Japan (ST, AH, and T Soga).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/4/13
Y1 - 2023/4/13
N2 - Oncometabolites, such as D/L-2-hydroxyglutarate (2HG), have directly been implicated in carcinogenesis; however, the underlying molecular mechanisms remain poorly understood. Here, we showed that the levels of the L-enantiomer of 2HG (L2HG) were specifically increased in colorectal cancer (CRC) tissues and cell lines compared with the D-enantiomer of 2HG (D2HG). In addition, L2HG increased the expression of ATF4 and its target genes by activating the mTOR pathway, which subsequently provided amino acids and improved the survival of CRC cells under serum deprivation. Downregulating the expression of L-2-hydroxyglutarate dehydrogenase (L2HGDH) and oxoglutarate dehydrogenase (OGDH) increased L2HG levels in CRC, thereby activating mTOR-ATF4 signaling. Furthermore, L2HGDH overexpression reduced L2HG-mediated mTOR-ATF4 signaling under hypoxia, whereas L2HGDH knockdown promoted tumor growth and amino acid metabolism in vivo. Together, these results indicate that L2HG ameliorates nutritional stress by activating the mTOR-ATF4 axis and thus could be a potential therapeutic target for CRC.
AB - Oncometabolites, such as D/L-2-hydroxyglutarate (2HG), have directly been implicated in carcinogenesis; however, the underlying molecular mechanisms remain poorly understood. Here, we showed that the levels of the L-enantiomer of 2HG (L2HG) were specifically increased in colorectal cancer (CRC) tissues and cell lines compared with the D-enantiomer of 2HG (D2HG). In addition, L2HG increased the expression of ATF4 and its target genes by activating the mTOR pathway, which subsequently provided amino acids and improved the survival of CRC cells under serum deprivation. Downregulating the expression of L-2-hydroxyglutarate dehydrogenase (L2HGDH) and oxoglutarate dehydrogenase (OGDH) increased L2HG levels in CRC, thereby activating mTOR-ATF4 signaling. Furthermore, L2HGDH overexpression reduced L2HG-mediated mTOR-ATF4 signaling under hypoxia, whereas L2HGDH knockdown promoted tumor growth and amino acid metabolism in vivo. Together, these results indicate that L2HG ameliorates nutritional stress by activating the mTOR-ATF4 axis and thus could be a potential therapeutic target for CRC.
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U2 - 10.1038/s41388-023-02632-7
DO - 10.1038/s41388-023-02632-7
M3 - Article
C2 - 36879117
AN - SCOPUS:85149366475
SN - 0950-9232
VL - 42
SP - 1294
EP - 1307
JO - Oncogene
JF - Oncogene
IS - 16
ER -
