Abstract
The stabilization of hypoxia inducible factor-1α (HIF-1α) protein plays an important role in the gene transcription in hypoxia. Overexpression of HIF-1α has been reported in various human cancers. It is degraded under normoxic conditions by proline hydroxylation through prolyl hydroxylase domain-containing protein (PHD), leading to von Hippel-Lindau (VHL) E3-ubiquitin ligase-mediated ubiquitination and rapid degradation by proteasome. Succinate is produced when PHD hydroxylates HIF-1α, implying that elevated succinate in normoxia represents an increase in PHD activity. We found that DNA methyltransferase (DNMT) inhibitor zebularine could downregulate HIF-1α expression in various colorectal cancer (CRC) cells. Zebularine enhanced the degradation of HIF-1α protein through inducing its hydroxylation. Metabolomic analysis showed that zebularine reversed the reduced succinate level in hypoxia, indicating an increase in PHD activity. Zebularine also reduced angiogenesis in CRC. Furthermore, zebularine potentiated the anticancer effect of oxaliplatin in CRC cells and in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC mouse model. This finding provides a new pharmacologic strategy to increase HIF-1α hydroxylation and overcome oxaliplatin resistance to enhance the anti-CRC therapy.
Citation Format: Ching-Chow Chen. Metabolic targeting of hypoxia and HIF-1α in colorectal cancer potentiates the therapeutic efficacy of oxaliplatin [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A075.
