The protein histidine phosphatase LHPP is a tumour suppressor

Abstract

Histidine phosphorylation, the so-called hidden phosphoproteome, is a poorly characterized post-translational modification of proteins. 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.

Clinical value of LHPP‐associated microRNAs combined with protein induced by vitamin K deficiency or antagonist‐II in the diagnosis of alpha‐fetoprotein‐negative hepatocellular carcinoma

“…In our study, the results here indicated that LHPP was markedly reduced in AFP‐NHCC cancer tissues, consistent with previous studies by Hindupur et al Targetscan, miRanda, miRDB, and TangetMiner software combined with luciferase reporter detection indicated that miR‐363‐5p and miR‐765 were involved in the targeted regulation of LHPP. Further, the current study screened miR‐363‐5p and miR‐765 to downregulate the expression of LHPP.…”

“…Therefore, identification of an effective diagnostic model for HCC is of great importance for patients, particularly for AFP‐NHCC patients. Recently, LHPP is reported to play an essential role in inhibiting human HCC progression by regulating phosphatidylinositol‐3‐kinase/protein kinase B (PI3K/AKT) signaling pathway, and the loss of LHPP expression is also associated with reduced survival in HCC . Zheng et al also found that LHPP expression levels were markedly reduced in human cervical cancer tissue samples compared to the adjacent normal tissue.…”

“…In 2018, Hindupur et al discovered a new HCC suppressor protein‐LHPP, in the mouse HCC model, and they also revealed its potential anticancer mechanism. They found that (a) with the development of HCC tumors, the expression of LHPP protein in mouse HCC cancer tissues gradually decreased, while the level of LHPP in the adjacent tissues was normal; (b) The Cancer Genome Atlas (TCGA) data showed that the severity of HCC and the life expectancy of patients were significantly correlated with the level of LHPP in the tissues, and the patients with low LHPP expression had a lower median survival time than those with high LHPP expression for nearly 2 years; (c) when the expression of LHPP in cells is downregulated, the level of proteomic phosphorylation in the cells is significantly increased, thereby causing uncontrolled cancer cell proliferation.…”

Recent Updates on Protein N‐Phosphoramidate Hydrolases

“…In 2018, Hindupur and co‐workers demonstrated that LHPP was a protein pHis hydrolase, with potential physiological substrates, including ACLY, histone H2A.V, and RNA polymeraseassociated protein LEO1 . These substrates were identified through immunoprecipitation with pHis‐specific antibodies from lysates of CB1 cells lacking LHPP.…”

“…Although these early reports of pLys hydrolase activities did not reveal the identity of the responsible enzymes, more recent studies found that PHPT1, which is best known as a protein pHis hydrolase, also dephosphorylated poly(pLys) and chemically Lys‐phosphorylated histone H1 . LHPP, another mammalian pHis phosphatase (see Section 3.2), also hydrolyzed pLys monomer, but it is unknown whether it is active towards pLys in protein substrates.…”