LncRNA IDH1-AS1 links the functions of c-Myc and HIF1α via IDH1 to regulate the Warburg effect

Significance We report in this article that c-Myc-mediated repression of lncRNA IDH1-AS1 sustains activation of the Warburg effect by HIF1α under normoxic conditions. IDH1-AS1 would otherwise enhance IDH1 enzymatic activity through promoting its homodimerization, leading to increased production of α-KG, which, along with decreases in ROS levels similarly resulting from increased IDH1 activity, causes down-regulation of HIF1a and a reduction in glycolysis. Collectively, our results have identified a signaling axis c-Myc-(IDH1-AS1)-IDH1-αKG/ROS-HIF1α that is important for activation of the Warburg effect under normoxia. Moreover, the results reveal IDH1 as a member of c-Myc-responsive metabolic enzymes and demonstrate that c-Myc plays an important part in balancing mitochondrial respiration and glycolysis to ensure glycolysis be executed efficiently in cancer cells under normoxia.
The oncoprotein c-Myc plays an important role in regulating glycolysis under normoxia; yet, in cancer cells, HIF1α, which is essential for driving glycolysis under hypoxia, is often up-regulated even in the presence of oxygen. The relationship between these two major regulators of the Warburg effect remains to be fully defined. Here we demonstrate that regulation of a long noncoding RNA (lncRNA), named IDH1-AS1, enables c-Myc to collaborate with HIF1α in activating the Warburg effect under normoxia. c-Myc transcriptionally repressed IDH1-AS1, which, upon expression, promoted homodimerization of IDH1 and thus enhanced its enzymatic activity. This resulted in increased α-KG and decreased ROS production and subsequent HIF1α down-regulation, leading to attenuation of glycolysis. Hence, c-Myc repression of IDH1-AS1 promotes activation of the Warburg effect by HIF1α. As such, IDH1-AS1 overexpression inhibited cell proliferation, whereas silencing of IDH1-AS1 promoted cell proliferation and cancer xenograft growth. Restoring IDH1-AS1 expression may therefore represent a potential metabolic approach for cancer treatment.