Multi-omics integration of methyltransferase-like protein family reveals clinical outcomes and functional signatures in human cancer

Abstract

Human methyltransferase-like (METTL) proteins transfer methyl groups to nucleic acids, proteins, lipids, and other small molecules, subsequently playing important roles in various cellular processes. In this study, we performed integrated genomic, transcriptomic, proteomic, and clinicopathological analyses of 34 METTLs in a large cohort of primary tumor and cell line data. We identified a subset of METTL genes, notably METTL1, METTL7B, and NTMT1, with high frequencies of genomic amplification and/or up-regulation at both the mRNA and protein levels in a spectrum of human cancers. Higher METTL1 expression was associated with high-grade tumors and poor disease prognosis. Loss-of-function analysis in tumor cell lines indicated the biological importance of METTL1, an m7G methyltransferase, in cancer cell growth and survival. Furthermore, functional annotation and pathway analysis of METTL1-associated proteins revealed that, in addition to the METTL1 cofactor WDR4, RNA regulators and DNA packaging complexes may be functionally interconnected with METTL1 in human cancer. Finally, we generated a crystal structure model of the METTL1–WDR4 heterodimeric complex that might aid in understanding the key functional residues. Our results provide new information for further functional study of some METTL alterations in human cancer and might lead to the development of small inhibitors that target cancer-promoting METTLs.

Structure, Activity and Function of the Dual Protein Lysine and Protein N-Terminal Methyltransferase METTL13

“…METTL13 has 157 mutations annotated in the Catalog of Somatic Mutations In Cancer (COSMIC) database (Figure 7) and it has been highlighted as the most mutated METTL protein in comprehensive transcriptomics cancer datasets [63]. However, as METTL13 is a dual 7BS domain MT it is also one of the larger 7BS MTs which can represent an explanation for the high number of annotated mutations.…”

The potential role of N7-methylguanosine (m7G) in cancer

“…METTL1 is overexpressed in glioma as compared with adjacent normal tissues and increases with increasing tumor grades. METTL1 also demonstrates a high level of genomic amplification in glioma [ 55 ]. METTL1 enhances the proliferation and growth of glioma, which may involve the tumor-related MAPK signaling pathway [ 56 ].…”

“…Since m7G-related tumor studies are still in the preliminary stage, the remaining tumor types are grouped together in this section. Several studies have revealed upregulated expression of METTL1 in other tumors, including invasive breast carcinoma (BRCA), kidney renal clear cell carcinoma (KIRC), prostate adenocarcinoma, rectal carcinoma, and uterine corpus endometrial carcinoma [ 55 , 56 , 81 , 82 ]. Additionally, METTL1 exhibits a high level of genomic amplification in various tumors including sarcoma and adrenocortical carcinoma [ 55 ].…”

“…Several studies have revealed upregulated expression of METTL1 in other tumors, including invasive breast carcinoma (BRCA), kidney renal clear cell carcinoma (KIRC), prostate adenocarcinoma, rectal carcinoma, and uterine corpus endometrial carcinoma [ 55 , 56 , 81 , 82 ]. Additionally, METTL1 exhibits a high level of genomic amplification in various tumors including sarcoma and adrenocortical carcinoma [ 55 ]. METTL1 is associated with a poor prognosis in KIRC and mesothelioma patients, while it is related to favorable survival in patients with ovarian serous cystadenocarcinoma [ 56 ].…”

“…METTL1 is associated with a poor prognosis in KIRC and mesothelioma patients, while it is related to favorable survival in patients with ovarian serous cystadenocarcinoma [ 56 ]. Based on data from functional analysis, METTL1 is likely to interrelate and function with various RNA regulators and DNA packaging complexes in human tumors [ 55 ]. Additionally, METTL1 is associated with sensitivity to 5-fluorouracil, and stable knockdown of METTL1 in HeLa cells effectively increases its cytotoxic effect [ 83 ].…”