肿瘤细胞在低氧应激下存活后获得了推动癌症进展的能力。为了探索脱氢酶对低氧响应的贡献，我们使用siRNA靶向163个脱氢酶编码基因，并发现谷氨酸脱氢酶1（GDH1）在调节结直肠癌（CRC）细胞低氧存活方面发挥了关键作用。我们观察到GDH1缺陷对CRC发生具有抑制作用，并且即使在缺氧下，也会削弱缺氧诱导因子1-alpha（HIF-1α）的稳定性。机制上，低氧引发p300的招募到GDH1，促进其在K503和K527处的乙酰化。K527处GDH1的乙酰化诱导了GDH1与EGLN1/HIF-1α的复合物的形成。相比之下，K503处GDH1的乙酰化增强了其与α-酮戊二酸（αKG）和谷氨酸的亲和力。这样看来，αKG是GDH1在缺氧状态下的产物，但缺氧刺激通过EGLN1/HIF-1α复合物逆转了GDH1的酶活性，使αKG的消耗增加，提高了HIF-1α的稳定性，从而促进了CRC的进展。临床上，低氧调节的GDH1 AcK503/527可以作为CRC进展的生物标志物，并且是CRC治疗的潜在靶点。©2023作者们。

Tumor cells surviving hypoxic stress acquire the ability to drive cancer progression. To explore the contribution of dehydrogenases to the low oxygen concentration response, we used siRNAs targeting 163 dehydrogenase-coding genes and discovered that glutamate dehydrogenase 1 (GDH1) plays a critical role in regulating colorectal cancer (CRC) cell survival under hypoxia. We observed that GDH1 deficiency had an inhibitory effect on CRC occurrence and impaired hypoxia-inducible factor 1-alpha (HIF-1α) stability even under hypoxia. Mechanistically, hypoxia triggered p300 recruitment to GDH1, promoting its acetylation at K503 and K527. GDH1 acetylation at K527 induced the formation of a GDH1 complex with EGLN1/HIF-1α; in contrast, GDH1 acetylation at K503 reinforced its affinity for α-ketoglutarate (αKG), and glutamate production. In line with this view, αKG is a product of GDH1 under normoxia, but hypoxia stimulation reversed GDH1 enzyme activity and αKG consumption by the EGLN1/HIF-1α complex, increasing HIF-1α stability and promoting CRC progression. Clinically, hypoxia-modulated GDH1 AcK503/527 can be used as a biomarker of CRC progression and is a potential target for CRC treatment.© 2023 The Authors.