Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, 4100 John R Street, HWCRC 815, Detroit, MI, 48201, USA.
Sci Rep. 2021 Jul 20;11(1):14784. doi: 10.1038/s41598-021-94019-5.
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 mG 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.
人类甲基转移酶样（METTL）蛋白将甲基基团转移到核酸、蛋白质、脂质和其他小分子上，随后在各种细胞过程中发挥重要作用。在这项研究中，我们对 34 种 METTL 在一大组原发性肿瘤和细胞系数据中进行了综合基因组、转录组、蛋白质组和临床病理分析。我们鉴定出一组 METTL 基因，特别是 METTL1、METTL7B 和 NTMT1，在多种人类癌症中具有高频的基因组扩增和/或 mRNA 和蛋白质水平的上调。更高的 METTL1 表达与高级别肿瘤和不良预后相关。在肿瘤细胞系中的功能丧失分析表明，mG 甲基转移酶 METTL1 在癌细胞生长和存活中具有重要的生物学意义。此外，METTL1 相关蛋白的功能注释和途径分析表明，除了 METTL1 共因子 WDR4 外，RNA 调节剂和 DNA 包装复合物可能与人类癌症中的 METTL1 在功能上相互关联。最后，我们生成了 METTL1-WDR4 异二聚体复合物的晶体结构模型，这可能有助于理解关键的功能残基。我们的研究结果为进一步研究人类癌症中某些 METTL 改变的功能提供了新信息，并可能导致开发针对促进癌症的 METTL 的小分子抑制剂。
