Peer Review #1 of "Role of methyltransferase-like enzyme 3 and methyltransferase-like enzyme 14 in urological cancers (v0.1)"

Abstract

N6-methyladenosine (m6A) modifications can be found in eukaryotic messenger RNA (mRNA), long non-coding RNA (lncRNA), and microRNA (miRNA). Several studies have demonstrated a close relationship between m6A modifications and cancer cells. Methyltransferase-like enzyme 3 (METTL3) and methyltransferase-like enzyme 14 (METTL14) are two major enzymes involved in m6A modifications that play vital roles in various cancers. However, the roles and regulatory mechanisms of METTL3 and METTL14 in urological cancers are largely unknown. In this review, we summarize the current research results for METTL3 and METTL14 and identify potential pathways involving these enzymes in kidney, bladder, prostate, and testicular cancer. We found that METTL3 and METTL14 have different expression patterns in four types of urological cancers. METTL3 is highly expressed in bladder and prostate cancer and plays an oncogenic role on cancer cells; however, its expression and role are opposite in kidney cancer. METTL14 is expressed at low levels in kidney and bladder cancer, where it has a tumor suppressive role. Low METTL3 or METTL14 expression in cancer cells negatively regulates cell growthrelated pathways (e.g., mTOR, EMT, and P2XR6) but positively regulates cell death-related pathways (e.g., P53, PTEN, and Notch1). When METTL3 is highly expressed, it positively regulates the NF-kB and SHH-GL1pathways but negatively regulates PTEN. These results suggest that although METTL3 and METTL14 have different expression levels and regulatory mechanisms in urological cancers, they control cancer cell fate via cell growthand cell death-related pathways. These findings suggest that m6A modification may be a potential new therapeutic target in urological cancer.