The protein histidine phosphatase LHPP is a tumour suppressor

Decreased expression of histidine phosphatase LHPP, a novel tumour suppressor, results in increased global histidine phosphorylation and hepatocellular carcinoma. Histidine phosphorylation is a poorly understood process involved in the post-translational modification of proteins. Michael Hall and colleagues have identified LHPP as a histidine phosphatase and provide evidence that it functions as a tumour suppressor in liver tumours. They find that patients with hepatocellular carcinoma and low levels of LHPP have reduced overall survival. 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.