Increased de novo nucleotide biosynthesis is required for cancer cell proliferation. However, it remains unclear how cancer cells obtain ribose-5-phosphate, glycine, glutamine, aspartate, and NADPH from glucose and glutamine metabolism to achieve increased de novo nucleotide biosynthesis. Mondo family transcription factors including MondoA and ChREBP play important roles in regulating glucose, lipid and amino acid metabolism. We recently identified a novel role of MondoA and ChREBP in promoting de novo nucleotide biosynthesis. In order to investigate the mechanism by which ChREBP and MondoA increased de novo nucleotide biosynthesis, we searched for target genes for ChREBP and MondoA which played critical roles in nucleotide biosynthesis. We found that transketolase (TKT), a target gene for Mondo family, could be important for nucleotide biosynthesis. TKT is a regulatory enzyme in the non-oxidative branch of pentose phosphate pathway and plays an important role in providing cancer cells with building blocks for de novo nucleotide biosynthesis.

We generated a liver specific TKT knockout mice strain by crossing TKTfl/fl mice with albumin (Alb)-Cre mice.2-week old male mice were injected 25mg/kg diethylnitrosamine (DEN), followed by high fat diet (HFD) feeding from one-month postbirth. We found that about 100% TKT+/+Alb-Cre and TKTfl/+Alb-Cre mice developed liver cancer whereas the tumor incidence decreased to 40% in TKTfl/fl Alb-Cre mice at 9 month postbirth. Tumor number and size were significantly reduced in TKTfl/fl Alb-Cre mice when compared to control littermates. Intriguingly, TKT deficiency reduced NADPH levels while promoting R5P production. Notably, loss of TKT in liver not only attenuated DEN/HFD-induced hepatic steatosis and fibrosis, but also led to increased apoptosis, reduced cell proliferation and decreased expression of TNF-a, IL-6 and Stat3. Our study may provide new strategies for liver cancer prevention and therapy through transcriptional and metabolic regulation.