In the 1920s, Otto H. Warburg discovered the metabolic hallmark of cancer: the Warburg effect. It describes that tumor cells have a high glucose consumption rate and produce large amounts of lactate.. It was difficult to understand why tumor cells need the Warburg effect since the generation and excretion of lactate would appear be a waste of carbon backbone and energy that is needed for proliferation. In one of Warburg’s milestone reviews, he proposed that the cause of the Warburg effect was injury of respiration and the consequence, cell dedifferentiation.  At that time, he was aware that inhibition of respiration led to metabolic reprograming and insightfully proposed a connection between metabolic reprograming and cell dedifferentiation, the underlying mechanism was unclear due to limited understanding of the connection between metabolism and epigenetic control.  

Our lab is interested in understanding how does metabolic reprogramming  induce the Warburg effect to alter epigenetic landscape in cancer cells and developing metabolic intervention strategies to overcome tumor resistance to differentiation therapy. 

Our research has revealed that hypoxia represses neuroblastoma cell differentiation by reducing cellular acetyl-CoA levels, leading to a decrease in global histone acetylation and chromatin accessibility. Supplementation with acetate or glycerol triacetate (GTA) restored chromatin accessibility, reactivating expression of differentiation markers and the neuron differentiation program under hypoxia (Cell Death & Disease, 2020). Additionally, we found that serine starvation in breast cancer cells also decreases cellular acetyl-CoA levels, reducing global histone acetylation and silencing estrogen receptor (ER) signaling. This can be restored by acetate or GTA supplementation (Li, et al., BioRxiv, 2021). These findings suggest that reducing pyruvate flux towards acetyl-CoA generation is the key to the Warburg effect, leading to decreased histone acetylation and shutting off lineage-specific gene expression.  
DNA methylation, which has a more stable and long-lasting effect on gene expression and cell fate control compared to histone modifications, is dysregulated in cancer patients and associated with poor prognosis, tumorigenesis, and therapeutic resistance. In the hypoxic tumor environment, the low NAD+/NADH ratio reduces α-KG, which forms L-2-hydroxyglutarate (L-2-HG) and inhibits TET DNA demethylase, blocking differentiation. The lower NAD+/NADH ratio also favors the conversion of pyruvate to lactate, promoting the Warburg effect. To address this, there is a need to increase the NAD+/NADH ratio and inhibit L-2-HG production.  We recently discovered that mitochondrial uncoupling effectively increases the NAD+/NADH ratio and α-KG/2-HG ratio, promoting global DNA demethylation, neuroblastoma cell differentiation, and N-Myc downregulation. These results suggest that mitochondrial uncoupling is an effective metabolic and epigenetic intervention that remodels the tumor epigenome for improved prognosis (Jiang, et al., Cancer Res, 2022).