The Identification of Zinc-Finger Protein 433 as a Possible Prognostic Biomarker for Clear-Cell Renal Cell Carcinoma

Abstract

Clear-cell renal cell carcinoma (ccRCC) is the most common and aggressive form of all urological cancers, with poor prognosis and high mortality. At late stages, ccRCC is known to be mainly resistant to chemotherapy and radiotherapy. Therefore, it is urgent and necessary to identify biomarkers that can facilitate the early detection of ccRCC in patients. In this study, the levels of transcripts of ccRCC from The Cancer Genome Atlas (TCGA) dataset were used to identify prognostic biomarkers in this disease. Analyzing the data obtained indicated that the KRAB-ZNF protein is significantly suppressed in clear-cell carcinomas. Furthermore, ZNF433 is differentially expressed in ccRCC in a stage- and histological-grade-specific manner. In addition, ZNF433 expression was correlated with metastasis, with greater node involvement associated with lower ZNF433 expression (p < 0.01) and with a more unsatisfactory overall survival outcome (HR, 0.45; 95% CI, 0.33–0.6; p = 8.5 × 10−8). Since ccRCC is characterized by mutations in proteins that alter epigenetic modifications and /or chromatin remodeling, we examined the expression of ZNF433 transcripts in ccRCC with wildtype and mutated forms of BAP1, KDMC5, MTOR, PBRM1, SETD2, and VHL. Analysis revealed that ZNF433 expression was significantly reduced in ccRCC with mutations in the BAP1, SETD2, and KDM5C genes (p < 0.05). In addition, the ZNF433 promoter region was highly methylated, and hypermethylation was significantly associated with mRNA suppression (p < 2.2 × 10−16). In silico analysis of potential ZNF target genes found that the largest group of target genes are involved in cellular metabolic processes, which incidentally are particularly impaired in ccRCC. It was concluded from this study that gene expression of ZNF433 is associated with cancer progression and poorer prognosis, and that ZNF433 behaves in a manner that suggests that it is a prognostic marker and a possible tumor-suppressor gene in clear-cell renal cell carcinoma.

Identification of IL20RB as a Novel Prognostic and Therapeutic Biomarker in Clear Cell Renal Cell Carcinoma

“…FGL1, fibrinogen-like protein 1, which is known as a novel potential immune checkpoint target [ 58 ], was recognized to be upregulated in tumor tissues and plasma specimens of ccRCC patients, and high FGL1 expression predicted a poor prognosis. In fact, there are many genes that have been identified as potential biomarkers in ccRCC, such as ZNF433 [ 59 ], AQP9 [ 60 ], SPINK13 [ 61 ], and DEF6 [ 62 ]. These works are different from each other for their interested and focused genes vary, but all genes identified are treasures for they have enhanced our understanding of ccRCC.…”

Prognostic Relevance of ZNF844 and Chr 19p13.2 KRAB-Zinc Finger Proteins in Clear Cell Renal Carcinoma

“…Clusters of closely related ZFPs are located on chromosomes 4, 7, 8, 10, 19, with the largest clusters located on the p and q arms of chromosome 19 (6,(31)(32)(33)(34)(35). We recently reported that ZNF433, a KRAB-ZFP located within a cluster found at chr19p13.2, is down-regulated in ccRCC, and its expression is closely associated with clinicopathological features of ccRCC (19). Given that there are several related KRAB-ZFPs CANCER GENOMICS & PROTEOMICS 19: 305-327 (2022) in this region, we examined whether these proteins were also differentially expressed in clear cell renal carcinoma.…”

“…Interestingly, several large KRAB-ZFP clusters are located on chromosome 19 (chr19), and several studies have linked genetic alterations in chromosome 19p13 to cancers (12)(13)(14)(15)(16)(17)(18). Using data mining techniques, we recently identified ZNF433, a zinc finger that is differentially expressed in ccRCC (19) and that may be a biomarker for ccRCC. ZNF433 is part of a cluster of KRAB-ZFPs that are located on chromosome 19p13.2.…”

The role of zinc finger proteins in malignant tumors

“…Furthermore, transcriptome profiling of KRAB‐ZNF‐expressing renal cancer (RCC) revealed a variety of stem cell markers, including ZNF2, ZNF256, ZNF585, and ZNF829, and they may act as prognosis predictors 104 . Additionally, ZNF433 is highly methylated in clear‐cell renal cell carcinoma (ccRCC), along with significantly decreased expression and mutations of BAP1, SETD2, and KDM5C genes, which are associated with metastasis 105 . As a consequence, ZNFs can be a prognostic marker in urinary‐related cancers.…”

“…104 Additionally, ZNF433 is highly methylated in clear-cell renal cell carcinoma (ccRCC), along with significantly decreased expression and mutations of BAP1, SETD2, and KDM5C genes, which are associated with metastasis. 105 As a consequence, ZNFs can be a prognostic marker in urinary-related cancers.…”