The N⁶‐methyladenosine (m⁶A) erasers alkylation repair homologue 5 (ALKBH5) and fat mass and obesity‐associated protein (FTO) are prognostic biomarkers in patients with clear cell renal carcinoma

Abstract

Objectives To comprehensively investigate the role of the N6‐methyladenosine (m6A) erasers ALKBH5 and FTO in clear cell renal cell carcinoma (ccRCC), other RCC subtypes, and oncocytoma with respect to prognostic value and biomarker potential. Patients and Methods The collection of tissue samples was performed within the framework of the Biobank at the Centre for Integrated Oncology Cologne‐Bonn. The gene expressions of alkylation repair homologue 5 (ALKBH5) and fat mass and obesity‐associated protein (FTO) were determined using quantitative real‐time polymerase chain reaction. ALKBH5 and FTO expressions were further investigated in ccRCC, papillary RCC, chromophobe RCC, sarcomatoid RCC, oncocytoma, and benign renal tissue using tissue microarrays. Results ALKBH5 mRNA, as well as ALKBH5 and FTO protein expressions, was significantly downregulated in ccRCC compared to normal tissue and most of the other studied tumour entities. Decreased mRNA levels of ALKBH5 and FTO correlated with a shortened overall and cancer‐specific survival following nephrectomy. Conclusions Taken together, our present data indicate that the m6A‐demethylases ALKBH5 and FTO are dysregulated in ccRCC and could be used as prognostic biomarkers.

The biological function of m6A demethylase ALKBH5 and its role in human disease

“…As for other cancers, ALKBH5 was significantly downregulated in clear cell renal cell carcinoma (ccRCC) compared to normal tissue [45]. It was also affirmed that ALKBH5 took a great part in contributing to osteosarcoma tumorigenesis [40].…”

“…Chu et al [32] and Feng et al [33] respectively identified the crystal structure of zebrafish ALKBH5 (fALKBH5) and human ALKBH5, which promoted the understanding of the substrate recognition specificity of ALKBH5 and offered a foundation for the development of inhibitors selective for NAOX. In addition, Xu et al [34] affirmed Clear cell renal cell carcinoma Downregulated --- [45] Osteosarcoma --Proliferation and tumor growth PVT1 [40] Oral squamous cell carcinoma --Chemoresistance FOXM1, NANOG [46] the m6A binding pocket of ALKBH5 and the key residues related with m6A recognition through mutagenesis and isothermal titration calorimetry binding experiments. Furthermore, m6A served as a 'conformational marker' , which induced different conformational outcomes in RNAs depending on sequence context and critically impacted its interactions with ALKBH5 [35].…”

The Emerging Roles of RNA Modifications in Glioblastoma

“…Methylation levels in miRNAs are also potential diagnostic biomarkers for early-stage gastrointestinal cancers [166]. The m 6 A erasers ALKBH5 and FTO are also shown to be prognostic biomarkers in patients with clear cell renal carcinoma [167]. From Table 1, some RNA modification enzymes are also tightly related to the grades and may predict the prognosis of GBM.…”

The Potential Roles of RNA N6-Methyladenosine in Urological Tumors

“…Strick et al conducted qRT-PCR to detect the gene expressions of ALKBH5 and FTO were studied in 166 ccRCC and 106 normal renal tissues. They found that the expression level of ALKBH5 and FTO were obviously decreased in ccRCC tissues (Strick et al, 2020). Declined mRNA levels of ALKBH5 and FTO were related to a shortened overall and cancer-specific survival following nephrectomy.…”