Diacetylation Mediated GDH1 Targeting EGLN1/HIF1α to Promote Colorectal Tumorigenesis

Abstract

To investigate the correlation between dehydrogenases and the hypoxia response, we used siRNA targeting 134 dehydrogenase-coding genes in HCT116 cells and discovered that glutamate dehydrogenase 1 (GDH1) plays a role in regulating cell survival under hypoxia. α-Ketoglutarate (αKG) is an important biological compound involved in the formation of amino acids, nitrogen transport, and oxidation reactions. There is no clear association between αKG and colorectal cancer (CRC), especially as the underlying molecular mechanisms of αKG-mediated CRC progression are still elusive. We observed that GDH1 deficiency had an inhibitory effect on the occurrence of CRC and impelled hypoxia-inducible factor 1-alpha (HIF1α) instability even under hypoxia. Mechanistically, hypoxia prompted GDH1 to recruit p300, which in turn acetylated GDH1 at K503 and K527. Acetylation at K527 (AcK527) induced the formation of a complex of GDH1 with EGLN1/HIF1α, while acetylation at K503 (AcK503) reinforced the affinity of GDH1 with αKG. Specifically, GDH1 AcK503 produced glutamate using αKG as a substrate, which would deplete αKG around the EGLN1/HIF1α complex, thus increasing HIF1α stability and promoting CRC progression. Clinically, hypoxia-modulated AcK503/527 of GDH1 can be used as a biomarker for the progression of CRC and is also a potential target for the treatment of CRC.

Keywords: α-Ketoglutarate, GDH1, acetylation, HIF1α, EGLN1, colorectal cancer