On March 21, 2018, a paper named “The protein histidine phosphatase LHPP is a tumour suppressor” published on the journal of Nature. In their study, they demonstrated that the loss of LHPP protein promoted tumor growth and reduced the chance of survival in cancer patients. LHPP may potentially serve as a prognostic biomarker.

By knocking out the PTEN and TSC1 genes and activating the mTOR signaling pathway, the researchers constructed an L-dKO mouse model that developed a macroscopic tumor at 16 weeks and developed liver cancer at 20 weeks. The results of the proteomic analysis showed that LHPP decreased slightly at 16 weeks and decreased significantly at 20 weeks in L-dKO mice. The researchers then did a further experiment which used adenoviral transfection and observed that injection of exogenous LHPP significantly inhibited the size and number of tumor cells at 20 weeks. From the clinical data, the researchers found that the survival of patients with low expression of LHPP was reduced by nearly 2 years. Using the TCGA and ICGC database, they also found that there were 49 LHPP mutation rates of 24.5% in a variety of cancers. These experimental results and clinical data all indicate that LHPP is a tumor suppressor gene.

With the further study of the mechanism of action of LHPP, they found that LHPP could remove the histidine-linked phosphate group in the protein. In the absence of LHPP, the histidine phosphorylation of the global protein increased, leading to the activation of several important functions and uncontrolled cell proliferation which promoted tumor growth and cancer.

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