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 clinicopatho...
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doaj-a96f1ed5472a45e0b580b21f83e4bdde2021-07-25T11:25:02ZengNature Publishing GroupScientific Reports2045-23222021-07-0111111410.1038/s41598-021-94019-5Multi-omics integration of methyltransferase-like protein family reveals clinical outcomes and functional signatures in human cancerIon John Campeanu0Yuanyuan Jiang1Lanxin Liu2Maksymilian Pilecki3Alvina Najor4Era Cobani5Morenci Manning6Xiaohong Mary Zhang7Zeng-Quan Yang8Department of Oncology, Wayne State University School of MedicineDepartment of Oncology, Wayne State University School of MedicineDepartment of Oncology, Wayne State University School of MedicineDepartment of Oncology, Wayne State University School of MedicineDepartment of Oncology, Wayne State University School of MedicineDepartment of Oncology, Wayne State University School of MedicineDepartment of Oncology, Wayne State University School of MedicineDepartment of Oncology, Wayne State University School of MedicineDepartment of Oncology, Wayne State University School of MedicineAbstract 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.https://doi.org/10.1038/s41598-021-94019-5 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ion John Campeanu Yuanyuan Jiang Lanxin Liu Maksymilian Pilecki Alvina Najor Era Cobani Morenci Manning Xiaohong Mary Zhang Zeng-Quan Yang |
spellingShingle |
Ion John Campeanu Yuanyuan Jiang Lanxin Liu Maksymilian Pilecki Alvina Najor Era Cobani Morenci Manning Xiaohong Mary Zhang Zeng-Quan Yang Multi-omics integration of methyltransferase-like protein family reveals clinical outcomes and functional signatures in human cancer Scientific Reports |
author_facet |
Ion John Campeanu Yuanyuan Jiang Lanxin Liu Maksymilian Pilecki Alvina Najor Era Cobani Morenci Manning Xiaohong Mary Zhang Zeng-Quan Yang |
author_sort |
Ion John Campeanu |
title |
Multi-omics integration of methyltransferase-like protein family reveals clinical outcomes and functional signatures in human cancer |
title_short |
Multi-omics integration of methyltransferase-like protein family reveals clinical outcomes and functional signatures in human cancer |
title_full |
Multi-omics integration of methyltransferase-like protein family reveals clinical outcomes and functional signatures in human cancer |
title_fullStr |
Multi-omics integration of methyltransferase-like protein family reveals clinical outcomes and functional signatures in human cancer |
title_full_unstemmed |
Multi-omics integration of methyltransferase-like protein family reveals clinical outcomes and functional signatures in human cancer |
title_sort |
multi-omics integration of methyltransferase-like protein family reveals clinical outcomes and functional signatures in human cancer |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2021-07-01 |
description |
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. |
url |
https://doi.org/10.1038/s41598-021-94019-5 |
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