HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity.

By Huafeng Zhang, Ping Gao, R. Fukuda, G. Kumar, B. Krishnamachary, K. Zeller, C. V. Dang, G. Semenza. Cancer Cell, 2007

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Many cancer cells are characterized by increased glycolysis and decreased respiration, even under aerobic conditions. The molecular mechanisms underlying this metabolic reprogramming are unclear. Here we show that hypoxia-inducible factor 1 (HIF-1) negatively regulates mitochondrial biogenesis and O(2) consumption in renal carcinoma cells lacking the von Hippel-Lindau tumor suppressor (VHL). HIF-1 mediates these effects by inhibiting C-MYC activity via two mechanisms. First, HIF-1 binds to and activates transcription of the MXI1 gene, which encodes a repressor of C-MYC transcriptional activity. Second, HIF-1 promotes MXI-1-independent, proteasome-dependent degradation of C-MYC. We demonstrate that transcription of the gene encoding the coactivator PGC-1beta is C-MYC dependent and that loss of PGC-1beta expression is a major factor contributing to reduced respiration in VHL-deficient renal carcinoma cells.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/67b74d7b4294ae29eeacf20c038f50710a5a2db7

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Citations in the corpus

MYC on the Path to Cancer (2012, background): “Myc induction of reactive oxygen species (ROS), presumably through its induction of mitochondrial biogenesis and increased metabolism, has been implicated in genomic instability (Egler et al., 2005; Gao et al., 2007; Vafa et al., 2002; Zhang et al., 2007).”
Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. (2010, background): “These results indicate that SIRT1 transcriptional repression is mediated by CtBP during hypoxia.”
Regulation of pyruvate metabolism and human disease (2013, background): “Furthermore, HIF1 upregulates MIX Interactor 1, a transcription factor that represses cMYC, leading to a decrease in mitochondria biogenesis and mass, further decreasing pyruvate oxidation [151, 154].”
Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression (2010, background): “Reconstitution with VHL resulted in degradation of HIF-1α and HIF2α and increased mitochondrial biogenesis and oxygen consumption (23).”
Myc's broad reach. (2008, background): “Recently Myc has been shown to promote oxidative phosphorylation as well as glycolysis through coordinate transcriptional control of the mitochondrial metabolic network (Zhang et al. 2007; Morrish et al. 2008).”
Metabolic control of cell death (2014, background): “Last, HIF-1 stimulates mitophagy and inhibits mitochondrial biogenesis (83, 84).”
Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. (2016, background): “, 2004), and HIF-1α can also promote c-Myc degradation (Zhang et al., 2007).”
HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. (2007, background): “Finally, by indirect modulation of c-Myc transcriptional activity (see below), chronic HIF activation decreases overall mitochondrial mass (Hervouet et al., 2005; Zhang et al., 2007).”
Hypoxia-Inducible Factor (HIF)-1 Regulatory Pathway and its Potential for Therapeutic Intervention in Malignancy and Ischemia (2007, background): “The decreased levels of C-MYC in these cancer cells were found ultimately to lead to increased glycolysis and decreased mitochondrial respiration, crucial characteristics of cancer cells that survive and proliferate in the hypoxic conditions of the tumor microenvironment [20].”
Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy (2012, background): “The switch from oxidative to reductive metabolism that is mediated by HIF-1 [44] has the effect of reducing cellular ROS levels [16, 44], which may increase resistance to cytotoxic chemotherapy [71].”
Hypoxia-inducible factors in stem cells and cancer (2009, positive): “HIF-1 inhibition of cMyc can also lead to decreased mitochondrial biogenesis [92].”