PKM2 promotes glucose metabolism and cell growth in gliomas through a mechanism involving a let-7a/c-Myc/hnRNPA1 feedback loop

// Wenkang Luan 1,* , Yingyi Wang 1,* , Xincheng Chen 1,* , Yan Shi 1,* , Jiajia Wang 1 , Junxia Zhang 1 , Jin Qian 2 , Ri Li 1 , Tao Tao 1 , Wenjin Wei 1 , Qi Hu 1 , Ning Liu 1 and Yongping You 1 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China 2 Department of Neurosurgery, People’s Hospital of Xuancheng City, Anhui, China * These authors contributed equally to this work Correspondence to: Yongping You, email: // Keywords : let-7a microRNA, c-Myc, hnRNPA1, PKM2, glucose metabolism, aerobic glycolysis, glioma Received : October 08, 2014 Accepted : February 04, 2015 Published : February 10, 2015 Abstract Tumor cells metabolize more glucose to lactate in aerobic or hypoxic conditions than non-tumor cells. Pyruvate kinase isoenzyme type M2 (PKM2) is crucial for tumor cell aerobic glycolysis. We established a role for let-7a/c-Myc/hnRNPA1/PKM2 signaling in glioma cell glucose metabolism. PKM2 depletion via siRNA inhibits cell proliferation and aerobic glycolysis in glioma cells. C-Myc promotes up-regulation of hnRNPA1 expression, hnRNPA1 binding to PKM pre-mRNA, and the subsequent formation of PKM2. This pathway is downregulated by the microRNA let-7a, which functionally targets c-Myc, whereas hnRNPA1 blocks the biogenesis of let-7a to counteract its ability to downregulate the c-Myc/hnRNPA1/PKM2 signaling pathway. The down-regulation of c-Myc/ hnRNPA1/PKM2 by let-7a is verified using a glioma xenograft model. These results suggest that let-7a, c-Myc and hnRNPA1 from a feedback loop, thereby regulating PKM2 expression to modulate glucose metabolism of glioma cells. These findings elucidate a new pathway mediating aerobic glycolysis in gliomas and provide an attractive potential target for therapeutic intervention.