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A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation
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A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation
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Journal Article
A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation
2016
Overview
Dietary fructose is primarily metabolized in the liver. Here we demonstrate that, compared with normal hepatocytes, hepatocellular carcinoma (HCC) cells markedly reduce the rate of fructose metabolism and the level of reactive oxygen species, as a result of a c-Myc-dependent and heterogeneous nuclear ribonucleoprotein (hnRNP) H1- and H2-mediated switch from expression of the high-activity fructokinase (KHK)-C to the low-activity KHK-A isoform. Importantly, KHK-A acts as a protein kinase, phosphorylating and activating phosphoribosyl pyrophosphate synthetase 1 (PRPS1) to promote pentose phosphate pathway-dependent
de novo
nucleic acid synthesis and HCC formation. Furthermore, c-Myc, hnRNPH1/2 and KHK-A expression levels and PRPS1 Thr225 phosphorylation levels correlate with each other in HCC specimens and are associated with poor prognosis for HCC. These findings reveal a pivotal mechanism underlying the distinct fructose metabolism between HCC cells and normal hepatocytes and highlight the instrumental role of KHK-A protein kinase activity in promoting
de novo
nucleic acid synthesis and HCC development.
Li
et al.
show that the c-Myc-dependent splicing switch from ketohexokinase-C (KHK-C) to KHK-A activates phosphoribosyl pyrophosphate synthetase 1 (PRPS1), resulting in enhanced
de novo
nucleic acid synthesis and hepatocellular carcinoma formation.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/105
/ 13/106
/ 13/109
/ 13/51
/ 13/89
/ 631/67
/ 82/29
/ 82/58
/ 82/80
/ 82/83
/ Biology
/ Carcinoma, Hepatocellular - enzymology
/ Carcinoma, Hepatocellular - pathology
/ Enzymes
/ Hepatoma
/ Heterogeneous-Nuclear Ribonucleoprotein Group F-H
/ Humans
/ Kinases
/ Liver Neoplasms - enzymology
/ Nucleic Acids - biosynthesis
/ Oncology
/ Phosphothreonine - metabolism
/ Proteins
/ Proto-Oncogene Proteins c-myc - metabolism
/ Reactive Oxygen Species - metabolism
