Oncometabolite 2-hydroxyglutarate destabilizes CDH1 to regulate quiescence and enhance chemotherapy sensitivity

Isocitrate dehydrogenase 1 mutation IDH1R132H generates the oncometabolite (R)-2-hydroxyglutarate (2-HG). However, the mechanisms underlying the better clinical outcomes in patients with IDH1 mutation remain elusive. Here, we report that 2-HG sensitizes chemotherapy by destabilizing Fizzy And Cell Division Cycle 20 Related 1(CDH1) and reducing the number of quiescent cells (G0 phase cells). IDH1R132H-harboring glioblastoma tissues have decreased CDH1, which can be induced by IDH1R132H overexpression or 2-HG treatment in U87MG cells. Mechanistically, 2-HG inhibits Prolyl Hydroxylase Domain-containing protein 1 (PHD1), which hydroxylates proline 431 of CDH1 to maintain its stability. 2-HG induces hypo-hydroxylation of CDH1, rendering it susceptible to CDK1-mediated phosphorylation at serine 151/163, followed by β-TrCP-mediated ubiquitination and proteasomal degradation. Notably, in vitro and in vivo experiments demonstrate that 2-HG induces CDH1 downregulation and reduces quiescent cell populations not only in glioblastoma cells but also in lung cancer and colorectal cancer cells, and consistently sensitizes tumor cells to chemotherapy. Our findings shed light on why IDH1 mutations correlate with better prognosis and highlight the translational potential of 2-HG as a chemotherapy sensitizer. Cancer cells often use abnormal metabolism to grow and resist treatment, especially glioblastoma (a type of brain cancer). Our study focused on 2-hydroxyglutarate (2-HG), a molecule produced by cancer cells with an IDH1 gene mutation. We found 2-HG makes cancer cells more sensitive to chemotherapy. Here’s how: 2-HG blocks an enzyme called PHD1, which normally keeps the protein CDH1 stable. When PHD1 is blocked, CDH1 breaks down faster. This reduces the number of “dormant” cancer cells—quiet cells that are hard to kill with chemo. Our finding explains why glioblastoma patients with the IDH1 mutation often respond better to treatment. It also suggests 2-HG or PHD1 could be new targets to improve chemotherapy outcomes for brain, lung, and colorectal cancer patients.