Reduced cytosolic carboxypeptidase 6 (CCP6) level leads to accumulation of serum polyglutamylated DNAJC7 protein: A potential biomarker for renal cell carcinoma early detection

Abstract

Renal cell carcinoma (RCC) is frequently diagnosed at advanced stages of disease, although early diagnosis has much favorable prognosis. This study assessed aberrant expression of cytosolic carboxypeptidase 6 (CCP6) leading to accumulation of serum polyglutamylated DNAJC7 as a biomarker for early RCC detection. A total of 835 RCCs, 143 chronic nephritis, 170 kidney stones and 415 health controls were collected for qRT-PCR, immunohistochemistry and Western blot analysis of CCP6 expression and mass spectrometry of DNAJC7 and polyglutamylated DNAJC7. The data showed that CCP6 expression was significantly decreased in 30 RCC tissues and that mass spectrometric and pull-down analysis identified DNAJC7 as a substrate of CCP6 and showed upregulated polyglutamylated-DNAJC7 (polyE-DNAJC7) in sera of RCC patients. The electrochemiluminescence immunoassay of large-scale serum samples from multi-institutes further confirmed the remarkable increase of polyE-DNAJC7 in 805 RCCs compared to that of 385 healthy controls (p < 0.001), 128 patients with chronic nephritis (p < 0.001), and 153 with kidney stone (p < 0.001). Serum level of DNAJC7-polyE protein was also associated with advanced RCC stage and grade in 805 patients. The data from the current study for the first time demonstrated increased serum polyglutamylated DNAJC7 as a potential biomarker for RCC early detection and association with advanced tumor stages and grade, which provides support of further polyglutamylation research in RCC.

Comparative Genomic Hybridization and Transcriptome Sequencing Reveal Genes with Gain in Acute Lymphoblastic Leukemia: JUP Expression Emerges as a Survival-Related Gene

“…In other types of cancer, such as breast and lung cancer, it was determined that TOX4 was highly expressed [ 113 ]; however, it has not yet been linked to LLA. No association with the expression of DNAJC7 (DnaJ heat shock protein family (Hsp40) member C7) has been reported; however, the accumulation in serum of DNAJC 7 was proposed as a potential biomarker in renal cell carcinoma early detection [ 114 ]. In the case of TTC25 , also known as ODAD4 (outer dynein arm docking complex subunit 4), it is characterized by its participation in mucociliary clearance [ 115 ].…”

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“…Polyglutamylation is a reversible posttranslational protein modification (PTM) of the γ-carboxyl groups of glutamate in a primary protein sequence by peptide-like bond linkage with the amino group of free glutamate, and further extendible to polyglutamate chains of variable length in target proteins [ 1 , 2 , 3 ]. Tubulins and nucleosome assembly proteins (NAPs) are well-known polyglutamylation targets [ 4 , 5 ]; however, recent studies have expanded the number of potentially polyglutamylated candidates to include proteins such as nucleoplasmin (NPM) [ 6 ], the DnaJ homolog subfamily C member 7 (DNJC7) [ 7 ] and the mitotic arrest deficient 2 (MAD2) [ 8 ]. The length of the glutamate side chains ranges from 1 to 20 residues, enabling the coding of diverse signals and thus the regulation of protein function [ 9 ].…”