The protein histidine phosphatase LHPP is a tumour suppressor
Menée à l'aide de modèles murins de carcinome hépatocellulaire, cette étude met en évidence des mécanismes par lesquels la phosphatase LHPP exerce une fonction de suppresseur de tumeurs
Histidine phosphorylation, the so-called hidden phosphoproteome, is a poorly characterized post-translational modification of proteins1,2. Here we describe a role of histidine phosphorylation in tumorigenesis. Proteomic analysis of 12 tumours from an mTOR-driven hepatocellular carcinoma mouse model revealed that NME1 and NME2, the only known mammalian histidine kinases, were upregulated. Conversely, expression of the putative histidine phosphatase LHPP was downregulated specifically in the tumours. We demonstrate that LHPP is indeed a protein histidine phosphatase. Consistent with these observations, global histidine phosphorylation was significantly upregulated in the liver tumours. Sustained, hepatic expression of LHPP in the hepatocellular carcinoma mouse model reduced tumour burden and prevented the loss of liver function. Finally, in patients with hepatocellular carcinoma, low expression of LHPP correlated with increased tumour severity and reduced overall survival. Thus, LHPP is a protein histidine phosphatase and tumour suppressor, suggesting that deregulated histidine phosphorylation is oncogenic.
Nature 2018