Enzyme of Endogenous Glucose Production (Gluconeogenesis) Promotes Tumor Cell Proliferation

Numerous metabolic enzymes have been shown to play roles in the progression of certain types of cancer primarily as a result of mutations in the genes encoding these enzymes. For example the genes encoding subunits of the TCA cycle and oxidative phosphorylation enzyme complex, succinate dehydrogenase (SDH), genes encoding two of the three forms of isocitrate dehydrogenase (IDH), and the gene encoding fumarate hydratase (commonly just fumarase) have all been found to be mutated in certain types of cancer. The altered functions of the mutant proteins drive metabolic pathways that stimulate cancer cell growth and proliferation.

A recent publication in the journal, Nature Cell Biology, demonstrate a critical role for the metabolic enzyme, fructose-1,6-bisphosphatase 1 (FBP1), in driving cancer cell proliferation:

Fructose-1,6-bisphosphatase 1 functions as a protein phosphatase to dephosphorylate histone H3 and suppresses PPARα-regulated gene transcription and tumour growth

Gluconeogenesis is the metabolic pathway, predominantly occurring in the liver, that is responsible for what is termed endogenous glucose production. This pathway occurs in the cytosol of the cell and is responsible for the conversion of the carbon atoms lactate, pyruvate, and alanine into glucose in the liver for delivery to the blood. During periods of fasting and stress, the hormones glucagon and epinephrine stimulate liver cells to carry out gluconeogenesis.

The results presented in this paper demonstrate that in response to stress, particularly to glucose deprivation, the eIF2α kinase, PERK phosphorylates fructose-1,6-bisphosphatase 1 (FBP1). The phosphorylation of FBP1 causes the normal tetrameric enzyme to dissociate into monomers. Monomeric FBP1 proteins have an exposed nuclear localization signal (NLS) allowing the enzyme to be transported into the nucleus. Within the nucleus FBP1 binds to the transcription factor, peroxisome proliferator-activated receptor alpha (PPARα). In a complex with PPARα, FBP1 dephosphorylates histone H3 (phosphorylated on threonine 11: H3T11) in the promoter region of several genes encoding metabolic enzymes. The dephosphorylation of H3T11 results in suppression of PPARα-mediated activation of genes whose encoded enzymes function in fatty acid β-oxidation and amino acid oxidation such as the ACAA2 (acetyl-CoA acyltransferase 2) and ACAD8 (isobutyryl-CoA dehydrogenase) genes, respectively.

In certain forms of cancer, such as in hepatocellular carcinomas, there is enhanced expression of the enzyme, UDP-N-acetylglucosamine:polypeptide β-N-acetylglucosaminyltransferase (more commonly just O-GlcNAc transferase, OGT) that is responsible for the O-GlcNAcylation of numerous nuclear and cytoplasmic proteins. OGT is known to O-GlcNAcylate FBP1 which results in inhibition of the phosphorylation of FBP1 by PERK. In cancer cells the result is that there is enhanced PPARα-mediated fatty acid β-oxidation providing increased energy needed for tumor cell proliferation.