Deciphering Warburg Effect: The Connection between Metabolism, Epigenetics and Tumor Differentiation

Abstract Text

Deciphering the Warburg effect: the connection between metabolism, epigenetics and tumor differentiation

Jiangbin Ye¹, Yang Li¹, Joshua Gruber², Ulrike Litzenburger³, Yiren Zhou¹, Yu Miao¹, Edward LaGory¹, Albert Li¹, Zhen Hu⁴, Lori Hart⁵, John Maris⁵, Howard Chang^3,6, Amato Giaccia¹

¹Department of Radiation Oncology, ²Department of Genetics and ³Center for Personal Dynamic Regulomes, Stanford University ⁴Olivia Consulting Service ⁵Children's Hospital of Philadelphia  ⁶Howard Hughes Medical Institute

The Warburg effect is a metabolic hallmark of all cancer cells, characterized by increased glucose uptake and glycolysis for lactate generation. The generation and excretion of lactate would appear be a waste of carbon backbone and energy that is needed for proliferation. It was proposed by Warburg that the cause and consequence of the Warburg effect were the injury of respiration and cell dedifferentiation, respectively. One common factor that damages mitochondrial respiration is hypoxia, which is a metabolic stress that blocks cell differentiation and promotes cancer progression. The underlying mechanism by which this occurs is poorly understood, and no effective therapeutic strategy has been developed to overcome this resistance to differentiation. Using a neuroblastoma (NB) differentiation model, we have discovered that hypoxia represses the differentiation induced by retinoic acid (RA) as demonstrated by loss of neuron differentiation markers and changes in cell morphology, associated with reduction of global histone acetylation, that are caused by the induction of pyruvate dehydrogenase kinases (PDKs). PDKs phosphorylate pyruvate dehydrogenase (PDH), thereby blocking pyruvate entry into the TCA cycle, reducing acetyl-CoA generation, and promoting the Warburg effect. Genetic and pharmaceutical inhibition of PDK restores histone acetylation and NB cell differentiation morphology. Acetate supplementation restores histone acetylation, along with differentiation markers expression and neuron differentiation. In addition, ATAC-Seq analysis demonstrated that hypoxia treatment significantly reduces global chromatin accessibility, which can be restored by acetate supplementation. These findings suggest that (1) combining RA and acetate supplementation represents a potentially effective therapeutic strategy for neuroblastoma treatment; (2) diverting pyruvate away from acetyl-CoA generation is a key mechanism by which the Warburg effect blocks cell differentiation.