RNA methylation, catalysed by a set of RNA methyltransferases (RNMTs), modulates RNA structures, properties, and biological functions. RNMTs are increasingly documented to be dysregulated in various human diseases, particularly developmental disorders and cancer. However, the genomic and transcriptomic alterations of RNMTs, as well as their functional roles in human cancer, are limited. In this study, we utilized an unbiased approach to examine copy number alterations and mutation rates of 58 RNMTs in more than 10,000 clinical samples across 32 human cancer types. We also investigated these alterations and RNMT expression level as they related to clinical features such as tumour subtype, grade, and survival in a large cohort of tumour samples, focusing on breast cancer. Loss-of-function analysis was performed to examine RNMT candidates with important roles in growth and viability of breast cancer cells. We identified a subset of RNMTs, notably TRMT12, NSUN2, TARBP1, and FTSJ3, that were amplified or mutated in a subset of human cancers. Several RNMTs were significantly associated with breast cancer aggressiveness and poor prognosis. Loss-of-function analysis indicated FTSJ3, a 2ʹ-O-Me methyltransferase, as a candidate RNMT with functional roles in promoting cancer growth and survival. A subset of RNMTs, like FTSJ3, represents promising novel targets for anticancer drug discovery. Our findings provide a framework for further study of the functional consequences of RNMT alterations in human cancer and for developing therapies that target cancer-promoting RNMTs in the future.

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.

SARS-CoV-2, an emerging coronavirus, has spread rapidly around the world, resulting in over ten million cases and more than half a million deaths as of July 1, 2020. Effective treatments and vaccines for SARS-CoV-2 infection do not currently exist. Previous studies demonstrated that nonstructural protein 16 (nsp16) of coronavirus is an S-adenosyl methionine (SAM)-dependent 2'-O-methyltransferase (2'-O-MTase) that has an important role in viral replication and prevents recognition by the host innate immune system. In the present study, we employed structural analysis, virtual screening, and molecular simulation approaches to identify clinically investigated and approved drugs which can act as promising inhibitors against nsp16 2 0-O-MTase of SARS-CoV-2. Comparative analysis of primary amino acid sequences and crystal structures of seven human CoVs defined the key residues for nsp16 2-O'-MTase functions. Virtual screening and docking analysis ranked the potential inhibitors of nsp16 from more than 4,500 clinically investigated and approved drugs. Furthermore, molecular dynamics simulations were carried out on eight top candidates, including Hesperidin, Rimegepant, Gs-9667, and Sonedenoson, to calculate various structural parameters and understand the dynamic behavior of the drug-protein complexes. Our studies provided the foundation to further test and repurpose these candidate drugs experimentally and/or clinically for COVID-19 treatment.

The development of targeted therapies that inhibit cancer-driving oncogenes has improved outcomes of patients diagnosed with lung adenocarcinoma (LUAD). In contrast, patients diagnosed with lung squamous cell carcinoma (LUSC) suffer worse survival outcomes and lack effective targeted treatment options. Identification of molecular drivers of LUSC to support development of targeted treatments is urgently needed. Addressing this need, the current report introduces the novel cancer gene SLIT- and NTRK-like family member 3 (SLITRK3) and its role in activating the neurotrophic receptor tyrosine kinase 3 (NTRK3) in LUSC cells. Multiple genome-wide data sets from patient samples were produced by us or downloaded from public databases to analyze tumor gene copy number aberrations, mRNA expression and associated survival outcomes. An accompanying mechanistic study employed LUSC cell lines and multiple methods, including in situ immunofluorescence, sphere-formation assay, and fluorescence-activated cell sorting analysis of the CD133-positive cell fraction. Altogether, the results indicate that gene amplification and consequent high expression of SLITRK3 in LUSC is associated with worse outcomes and induces SLITRK3-dependent activation of NTRK3 to promote a cancer stem cell phenotype that is inhibited by existing NTRK-targeted inhibitors. Based on a recent literature search, this is the first report of a mechanistic role for SLITRK3 in cancer.