N⁶‐Methyladenosine (m⁶A) readers are dysregulated in renal cell carcinoma

Abstract

N6‐Methyladenosine (m6A) is the most common modification of messenger RNA (mRNA) in mammals. It critically influences RNA metabolism and plays an essential role in virtually all types of bioprocesses including gene expression, tissue development, self‐renewal and differentiation of stem cells, stress response and circadian clock control. It plays a crucial role in carcinogenesis and could be used as a prognostic and a diagnostic tool and as a target for new anticancer therapies. m6A modification is dynamically and reversibly regulated by three types of proteins. Methyltransferases, so‐called “writers” add a methyl group to the adenosine, which can be removed by demethylases, also called “erasers.” m6A‐specific RNA‐binding proteins, from here on referred to as “readers,” preferentially bind to the m6A site and mediate biological functions, such as translation, splicing or decay of RNA. In this study, we examined the expression of the six m6A readers HNRNPA2B1, HNRNPC, YTHDC1 and YTHDF1‐3 in clear cell renal carcinoma (ccRCC). We show that on mRNA level the expression of all six m6A readers is significantly downregulated compared to normal renal tissue and on protein level five out of six readers are dysregulated. Lower levels of some m6A readers are correlated with advanced stage and grade as well as associated with a shorter overall, progression‐free and cancer‐specific survival. In summary, we could show that m6A readers are dysregulated in ccRCC and might therefore act as a tumor marker, could give further information on the individual prognosis and be a target of innovative cancer therapy.

Gene Characteristics and Prognostic Values of m6A RNA Methylation Regulators in Nonsmall Cell Lung Cancer

“…It is known as m 6 A modification closely related to RNA splicing, localization, stability, export, RNA-protein interactions, alternative polyadenylation, and translation [11][12][13]. e cellular m 6 A methylation is mediated by a group of regulatory enzymes including "writers" Wilms' tumor 1-associated protein (WTAP), methyltransferase-like 3 (METTL3) and METTL14, "erasers" fat mass and obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5), and "readers" YTH domain containing 1 (YTHDC1/2) and YTH N 6 -methyladenosine RNA binding protein 1/2/3 (YTHDF1/ 2/3) [14][15][16]. Generally, m 6 A methylation is increased by writers, erased by FTO or ALKBH5, and deciphered by YTHDF1/2/3 or YTHDC1/2.…”

“…In recent years, growing evidences indicated that m 6 A dysregulation plays critical roles in tumorigenesis and cancer progression through diverse molecular mechanisms [14][15][16][17][18]. Meanwhile, the expression level of m 6 A-related regulatory proteins has been shown to be critically involved in tumorigenesis [19][20][21].…”

m6A readers, writers, erasers, and the m6A epitranscriptome in breast cancer

“…m6A readers with known relevance to BC, their cellular location, and molecular functions are summarized in Table 3. These m6A readers have been shown to play a role in embryonic stem cell fate (Batista et al 2014, Lasman et al 2020) energy homeostasis (Edupuganti et al 2017), human circadian rhythm (Robinson et al 2019), and various cancers (Jing et al 2021, von Hagen et al 2021. Evidence suggesting that the dysregulation of m6A readers plays a pivotal role in BC progression will be described below.…”

Roles and mechanisms of the m6A reader YTHDC1 in biological processes and diseases

“…It is estimated that in 2021 approximately 76,080 new cases would be identified in the United States and approximately 80% of the renal cancer are clear cell renal carcinoma [ 19 ]. Hagen et al performed a single-center study by analyzing the tissue samples from patients who underwent radical or partial nephrectomy at the Department of Urology at the University Hospital Bonn and reported that YTHDC1 was significantly downregulated in clear cell renal carcinoma compared to normal tissue in both mRNA and protein level [ 44 ]. Moreover, the dysregulated expression of YTHDC1 was associated with worse outcome, demonstrating that YTHDC1 may have the potential role as a biomarker and target for cancer treatment.…”