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

Ion John Campeanu,Xiaohong Mary Zhang,Yuanyuan Jiang,Era Cobani,Lanxin Liu,Morenci Manning,Zeng-Quan Yang,Maksymilian Pilecki,Alvina Najor

doi:10.1038/s41598-021-94019-5

Ion John Campeanu, Xiaohong Mary Zhang + Show 7 more

Open Access

https://doi.org/10.1038/s41598-021-94019-5

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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.

Highlights

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
We found that METTL1, METTL7B, and NTMT1 were overexpressed, while METTL7A and METTL24 were under-expressed in the CPTAC–LUAD tumors compared to normal adjacent tissue (NAT) (Fig. 2B, Supplementary Fig. S2A)
We found that high expression of METTL1, NTMT1, METTL26, and METTL7B was significantly associated with poor disease prognosis, while high METTL7A expression was associated with favorable progression in the LUAD cohort (Fig. 3B,C, Supplementary Fig. S4)

Summary

Introduction

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. 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. Human methyltransferase-like (METTL) proteins belong to a superfamily of S-adenosyl methionine (SAM)dependent enzymes that transfer methyl groups to nucleic acids, proteins, lipids, and small m olecules[1]. The availability of genomic, transcriptomic, and proteomic profiles across a broad range of cancers from TCGA (The Cancer Genome Atlas) and CPTAC (Clinical Proteomic Tumor Analysis Consortium) projects, as well as large-scale loss-of-function screens of cancer cell lines, provide an unprecedented opportunity to investigate genetic and proteomic alterations of METTLs associated with molecular signatures, clinical prognosis, and their functional importance in cancer in great depth.

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