Myc Posttranscriptionally Induces HIF1 Protein and Target Gene Expression in Normal and Cancer Cells

Abstract

c-Myc is frequently overexpressed in tumors and plays an important role in the regulation of cancer metabolism. Hypoxia-inducible factor-1 (HIF1), the master regulator of the hypoxic response, enhances tumorigenesis and influences metabolism via upregulation of the glycolytic pathway and suppression of mitochondrial respiration. Together, deregulated Myc and HIF1 cooperate to lend metabolic advantages to proliferating cancer cells and contribute to the Warburg Effect. Here we show that overexpression of Myc significantly stabilizes the alpha subunit of HIF1 (HIF1alpha) under normoxic conditions and enhances HIF1alpha accumulation under hypoxic conditions in cells. Post-transcriptional regulation of HIF1α by Myc led to the induction of HIF1α gene targets. Normoxic HIF1α protein expression was also dependent on Myc. Functionally; HIF1α expression was required for Myc-induced anchorage-independent growth and cell proliferation. Myc-dependent stabilization of HIF1α involved either disruption of binding to the VHL complex or post-translational protein modifications. Taken together, our findings uncover a previously uncharacterized regulatory relationship between Myc and HIF1 that has important implications for cancer metabolism and development.

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

“…The latter includes PDK1 that, as mentioned above, may play a role in the metabolic inhibition of PHDs so one can speculate that the miR-210-mediated upregulation of MYC represents a mechanism to amplify HIF activity [43]. Since MYC has also been reported to support HIF-1 directly by interfering with the VHL-dependent degradation of HIF-1a, these finding suggest the existence of MYC-mediated feedforward loops in the HIF pathway [44]. Intriguingly, however, HIF and MYC are traditionally considered to have antagonistic effects in the hypoxic cell.…”

The Soy Isoflavone Equol May Increase Cancer Malignancy via Up-regulation of Eukaryotic Protein Synthesis Initiation Factor eIF4G

“…The c-Myc transcription factor is one of the most important somatically mutated oncogenes in human cancer and confers a selective advantage to cancer cells by promoting protein synthesis, proliferation, cell survival, differentiation, genetic instability, angiogenesis, hypoxia-mediated cancer progression, and metastasis (33,33,47,(62)(63)(64)(65)(66). Studies have shown that c-Myc up-regulates both eIF4E and eIF4G gene expression (58).…”

Liposome-mediated Induction of Apoptosis of Human Hepatoma Cells by C-Myc Antisense Phosphorothioate Oligodeoxynucleotide and 5-Fluorouracil

“…Results from assays on c-myc mRNA and proteins indicated that 5-FU also could inhibit c-myc expression, possibly contributing to inhibition of 5-FU in liver cancer cells. This illustrates that c-myc can be used as a target of multiple antitumor drugs (Wang et al, 2012, Doe at al., 2012.…”