Deregulated histidine phosphorylation may promote tumorigenesis in hepatocellular carcinoma (HCC).
Major finding: Deregulated histidine phosphorylation may promote tumorigenesis in hepatocellular carcinoma (HCC).
Clinical relevance: LHPP is downregulated in patients with HCC, and the histidine kinases NME1 and NME2 are overexpressed.
Impact: LHPP loss promotes HCC tumorigenesis, and LHPP may be a tumor suppressor in a variety of tumor types.
Histidine phosphorylation is less well understood than post-translational phosphorylation of other residues. Hindupur and colleagues uncovered a role for histidine phosphorylation in liver tumorigenesis using a mouse model of mTOR-driven hepatocellular carcinoma (HCC), induced by liver-specific deletion of Pten and Tsc1 (L-dKO mice). Proteomic analysis of 12 mouse tumors revealed an upregulation of the only two known mammalian histidine kinases, NME1 and NME2, as well as downregulation of a putative histidine phosphatase, LHPP. In L-dKO tumors, expression of NME1/2 was mTOR-dependent, whereas LHPP expression was mTOR-independent. In vitro experiments confirmed that LHPP is a bona fide histidine phosphatase, and LHPP expression impaired cell proliferation in vitro and suppressed tumor formation to maintain normal liver function in vivo, indicating that LHPP is a tumor suppressor. Consistent with these findings in mouse tumors, LHPP was expressed at low levels in tumors from patients with HCC compared with adjacent normal tissue, whereas NME1 and NME2 were highly expressed in tumors. Further, in patients with HCC, LHPP downregulation was associated with accelerated disease progression and poorer survival. Analysis of data from The Cancer Genome Atlas and the International Cancer Genome Consortium revealed LHPP mutations in a variety of tumor types, suggesting that the tumor-suppressive role of LHPP may not be limited to HCC. In addition to identifying LHPP as a histidine phosphatase and tumor suppressor, these findings indicate that deregulated histidine phosphorylation is oncogenic in HCC and other tumor types.
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