Abstract 2180: Deciphering the Warburg effect: Redox is the key to tumor differentiation

Abstract It was proposed by Warburg that the cause and consequence of the Warburg effect were the injury of respiration and cell dedifferentiation, respectively. However, the underlying mechanism was unclear due to limited understanding of metabolic control of epigenetics. Inhibition of mitochondrial electron transport chain (ETC) causes reduction of NAD+/NADH ratio. Recently it was discovered that this redox stress not only drives lactate production from pyruvate to enhance the Warburg effect, but also promotes the conversion of α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), turning the substrate of DNA demethylase TET into an inhibitor of TET, suggesting a potential link between ETC inhibition and dysregulated DNA methylation in cancer. In this study we use a mitochondrial uncoupler niclosamide ethanolamine (NEN) to block the Warburg effect and remodel cancer epigenome. NEN treatment activates ETC and accelerates glutaminolysis to produce αKG, which promotes promoter CpG island demethylation. This epigenomic reprograming not only upregulates tumor suppressor genes such as p53, inhibits N-Myc expression, but also activates neuron differentiation markers to promote differentiation in neuroblastoma cells. Hypoxia is one common microenvironmental stress existing in all solid tumor. NEN treatment reduces 2HG generation from αKG under hypoxia, highlighting its application potential in preventing DNA hypermethylation in vivo. Associated with 2HG reduction, NEN treatment also represses HIF signaling under hypoxia. In addition, NEN treatment inhibits reductive carboxylation flux. Moreover, dietary supplementation with NEN reduces orthotopic neuroblastoma growth and N-Myc expression in vivo. Together, these results validated Warburg’s hypothesis that mitochondrial respiration is the key to maintain normal differentiation. Restoring ETC activity with mitochondrial uncoupler is an effective metabolic/epigenetic therapy against neuroblastoma (Jiang et al., BioRxiv 2021). Citation Format: Jiang Haowen, Rachel L. Greathouse, Bo He, Yang Li, Albert M. LI, Balint Forgo, Selene Banuelos, Joshua Gruber, Hiroyuki Shimada, Bill Chiu, Jiangbin Ye. Deciphering the Warburg effect: Redox is the key to tumor differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2180.