L-2hydroxyglutaric acid rewires amino acid metabolism in colorectal cancer via the mTOR-ATF4 axis

Sho Tabata, Yasushi Kojima, Takeharu Sakamoto, Kaori Igarashi, Ko Umetsu, Takamasa Ishikawa, Akiyoshi Hirayama, Rie Kajino-Sakamoto, Naoya Sakamoto, Ken ichi Yasumoto, Keiichi Okano, Yasuyuki Suzuki, Shinichi Yachida, Masahiro Aoki, Tomoyoshi Soga

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1294-1307
Number of pages14
JournalOncogene
Volume42
Issue number16
DOIs
Publication statusPublished - 2023 Apr 13

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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