Despite the fact that Otto H. Warburg discovered the Warburg effect almost one hundred years ago, why
cancer cells waste most of the
glucose carbon as
lactate remains an enigma. Warburg proposed a connection between the Warburg effect and cell dedifferentiation.
Hypoxia is a common
tumor microenvironmental stress that induces the Warburg effect and blocks
tumor cell differentiation. 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 differentiation model, we discovered that
hypoxia repressed cell differentiation through reducing cellular
acetyl-CoA levels, leading to reduction of global
histone acetylation and
chromatin accessibility. The metabolic switch triggering this global
histone hypoacetylation was the induction of
pyruvate dehydrogenase kinases (PDK1 and PDK3). Inhibition of PDKs using dichloroacetate (DCA) restored
acetyl-CoA generation and
histone acetylation under
hypoxia. Knocking down PDK1 induced
neuroblastoma cell differentiation, highlighting the critical role of PDK1 in cell fate control. Importantly,
acetate or
glycerol triacetate (GTA) supplementation restored
differentiation markers expression and neuron differentiation under
hypoxia. Moreover, ATAC-Seq analysis demonstrated that
hypoxia treatment significantly reduced
chromatin accessibility at RAR/RXR binding sites, which can be restored by
acetate supplementation. In addition,
hypoxia-induced
histone hypermethylation by increasing
2-hydroxyglutarate (2HG) and reducing α-ketoglutarate (αKG). αKG supplementation reduced
histone hypermethylation upon
hypoxia, but did not restore
histone acetylation or
differentiation markers expression. Together, these findings suggest that diverting
pyruvate flux away from
acetyl-CoA generation to
lactate production is the key mechanism that Warburg effect drives dedifferentiation and
tumorigenesis. We propose that combining differentiation
therapy with
acetate/GTA supplementation might represent an effective
therapy against
neuroblastoma.