p53 regulates purine and glucose metabolism by microRNA-34a

Abstract

p53 is a well-known transcription factor that controls cell cycle arrest and cell death in response to a wide range of stresses. Moreover, p53 has been emphasized as a metabolic regulator involved in glucose, glutamine and fatty acid. p53 mutations are observed in about half of cancer cases, and metabolic abnormalities are a distinct feature in tumor cells. Cancer cells rely mainly on glycolysis rather than mitochondrial respiration for energy production, which is called the Warburg effect. First, we demonstrated that p53-inducible microRNA-34a (miR-34a) repressed inosine 5-monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme of de novo GTP biosynthesis. Nucleotide biosynthesis is also critical for cell proliferation and the cell division cycle. Nonetheless, little is known about whether p53 regulates nucleotide biosynthesis. Treatment with anti-miR-34a inhibitor relieved the expression of IMPDH upon DNA damage. Ultimately, miR-34a-mediated inhibition of IMPDH resulted in repressed activation of the GTP-dependent Ras signaling pathway. In summary, we suggest that p53 has a novel function in regulating purine biosynthesis, aided by miR-34a-dependent IMPDH repression. Second, we demonstrated metabolic changes in cancer that occurred through p53. We found that p53-inducible microRNA-34a (miR-34a) repressed glycolytic enzymes (hexokinase 1, hexokinase 2, glucose-6-phosphate isomerase), and pyruvate dehydrogenase kinase 1. Treatment with an anti-miR-34a inhibitor relieved the decreased expression in these enzymes following DNA damage. miR-34a-mediated inhibition of these enzymes resulted in repressed glycolysis and enhanced mitochondrial respiration. The results suggest that p53 has a miR-34a-dependent integrated mechanism to regulate glucose metabolism.