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

Isocitrate dehydrogenase 1 mutation IDH1^R132H 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). IDH1^R132H-harboring glioblastoma tissues have decreased CDH1, which can be induced by IDH1^R132H 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.