Nuclear expression and clinical significance of phosphohistidine phosphatase 1 in clear-cell renal cell carcinoma

Abstract

Objective: To explore expression and clinical relevance of phosphohistidine phosphatase 1 (PHPT1) in clear-cell renal cell carcinoma. Methods: Patients with clear-cell renal cell carcinoma who underwent radical or nephron-sparing nephrectomy were enrolled. Correlations between PHPT1 expression and demographic and clinical characteristics were analysed prospectively. Results: In total, 122 patients (78 male/44 female) were included. In normal kidney tissue, PHPT1 expression was observed only in the proximal tubule. High PHPT1 expression levels were associated with larger tumour size, higher Fuhrman nuclear grade and advanced pathological tumour-node-metastasis (pTNM) stage compared with low PHPT1 expression levels. Patients with low PHPT1 expression showed better overall survival and progression-free survival compared with those with high PHPT1 expression. In addition, multivariate analysis showed that nuclear grade and pTNM stage were independent predictors of progression-free survival and overall survival in patients with clear-cell renal cell carcinoma. PHPT1 expression was also an independent predictor of overall survival but not progression-free survival. Conclusions: PHPT1 was expressed in the epithelium of proximal tubuli and nuclei of clear-cell renal cell carcinoma tissue samples. High levels of 14 kDa phosphohistidine phosphatase protein were negatively associated with overall survival and progression-free survival in patients with clear-cell renal cell carcinoma.

Redox inhibition of protein phosphatase PP2A: Potential implications in oncogenesis and its progression

“…Recently, a novel family of phosphatases has been identified that lends itself to the dephosphorylation of phosphohistidine residues [6]. This phosphatase is not well studied yet but seems to play a vital role in some cancers as well as insulin signaling [7], [8], [9]…”

Strong anion exchange‐mediated phosphoproteomics reveals extensive human non‐canonical phosphorylation

“…Until recently, phosphorylation of the hydroxyl‐containing amino acids serine (Ser), threonine (Thr) and tyrosine (Tyr) was thought to be the primary mode of phosphorylation‐mediated signalling in non‐plant eukaryotes. However, a growing body of evidence (Besant & Attwood, ; Fan et al , ; Fraczyk et al , ; Fuhs et al , ; Shen et al , ; Wieland & Attwood, ; Panda et al , ; Srivastava et al , ; Xu et al , ,b; Fuhs & Hunter, ) indicates that phosphorylation of other amino acids, termed here “non‐canonical” phosphorylation, including His, Asp, Glu, Lys, Arg and Cys [in addition to pyrophosphorylation of Ser and Thr to form ppSer and ppThr (Chanduri et al , ; Harmel & Fiedler, ), and Lys polyphosphorylation (Bentley‐DeSousa & Downey, )], may also regulate protein signalling functions. Of note, the generation of both site‐specific and generic antibodies against phosphohistidine (pHis) (Kee et al , , ; Fuhs et al , ; Lilley et al , ) has recently allowed mammalian cell‐type independent roles for this PTM to be elucidated (Fuhs et al , ) in processes as diverse as ion channel regulation (Srivastava et al , ) and T‐cell signalling (Panda et al , ), and during cell proliferation, differentiation and migration.…”

Extensive non-canonical phosphorylation in human cells revealed using strong-anion exchange-mediated phosphoproteomics

“…Until recently, phosphorylation of the hydroxyl-containing amino acids serine (Ser), threonine (Thr) and tyrosine (Tyr) was thought to be the primary mode of phosphorylation-mediated signalling in non-plant eukaryotes. However, a growing body of evidence [3][4][5][6][7][8][9][10][11][12][13] indicates that phosphorylation on the imidazolecontaining amino acid histidine (His) also plays a significant, but ill-defined, role in human biology. In contrast, and despite occasional reports in the literature 14,15 , the prevalence (or otherwise) of noncanonical amino acid phosphorylation on the five amino acids for which protein phosphorylation is chemically feasible (Asp, Arg, Lys, Glu, Cys) has yet to be revealed in human cells.…”