Potential role of the N-MYC downstream-regulated gene family in reprogramming cancer metabolism under hypoxia
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Ga Young Lee1, Yang-Sook Chun1,3, Hyun-Woo Shin1,2,3 and Jong-Wan Park1,2,3
1 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
2 Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea
3 Ischemic/Hypoxic Disease Institute and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
Jong-Wan Park, email:
Keywords: cancer, metabolic reprogramming, hypoxia, NDRG
Received: April 24, 2016 Accepted: June 13, 2016 Published: July 18, 2016
Metabolic reprogramming toward aerobic glycolysis and lactate fermentation supplies cancer cells with intermediate metabolites, which are used as macromolecule precursors. The oncogene MYC contributes to such aerobic metabolism by activating the expression of numerous genes essential for glycolysis and mitochondrial biogenesis. However, to survive and evolve in a hypoxic tumor milieu, cancer cells must revise MYC-driven metabolism because the mitochondrial respiratory chain provides free electrons to generate oxygen free radicals with inefficient production of ATP due to oxygen depletion. Instead, hypoxia-inducible transcription factor hypoxia-inducible factor 1 (HIF-1) takes over the role of MYC in glycolysis, but suppresses mitochondrial biogenesis and activity to protect cells from such threats. Recently, the N-MYC downstream-regulated gene (NDRG) family has received attention as potential biomarkers of cancer prognosis. NDRGs are repressed MYC-dependently in various cancers, but induced under hypoxia because HIF-1 directly activates their promoters and indirectly de-represses them by antagonizing MYC. In this review, we summarize the current understanding of the reprogramming of cancer metabolism via the counterbalance between MYC and HIF-1, and discuss the proven and putative roles of the NDRG family in adjusting cancer metabolism according to the ambient oxygen level.
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