Glutamate dehydrogenase1 supports HIF‐1α stability to promote colorectal tumorigenesis under hypoxia
Glutamate dehydrogenase1 supports HIF‐1α stability to promote colorectal tumorigenesis under hypoxia
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DOI：
10.15252/embj.2022112675
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发表时间：
2023-04
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通讯作者：
Kunhua Hu;Yufeng Ding;Hongwen Zhu;Xiaoqian Jing;Wei-ling He;Hua Yu;Xiongjun Wang
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作者：
Kunhua Hu;Yufeng Ding;Hongwen Zhu;Xiaoqian Jing;Wei-ling He;Hua Yu;Xiongjun Wang
在缺氧胁迫下存活的肿瘤细胞获得了驱动癌症进展的能力。为了探索脱氢酶在低氧浓度应答中的作用，我们使用靶向163个脱氢酶编码基因的sirna，发现谷氨酸脱氢酶1 （GDH1）在低氧条件下调节结直肠癌（CRC）细胞存活中起关键作用。我们观察到GDH1缺乏对结直肠癌的发生和缺氧诱导因子1α (HIF - 1α)稳定性的损害具有抑制作用，即使在缺氧条件下。在机制上，缺氧触发p300募集到GDH1，促进其在K503和K527的乙酰化。GDH1在K527位点乙酰化诱导GDH1与EGLN1/HIF‐1α形成复合物；相比之下，GDH1在K503位点的乙酰化增强了其对α‐酮戊二酸（α kg）和谷氨酸生成的亲和力。与此观点一致，αKG是常氧下GDH1的产物，但缺氧刺激逆转了GDH1酶活性和EGLN1/HIF‐1α复合物对αKG的消耗，增加了HIF‐1α的稳定性，促进了结直肠癌的进展。在临床上，缺氧调节的GDH1 AcK503/527可作为结直肠癌进展的生物标志物，是结直肠癌治疗的潜在靶点。
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.