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Access Type
WSU Access
Date of Award
January 2025
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Cancer Biology
First Advisor
Zeng-Quan Yang
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 Aim 1, we performed integrated genomic, transcriptomic, proteomic, and clinicopathological analyses of 34 METTLs in a cohort of primary tumor and cell line data. We identified a subset of METTL genes, notably METTL1, TMT1B, and NTMT1, with high frequencies of genomic amplification and/or up-regulation at the mRNA and protein levels in multiple human cancers. Higher METTL1 expression was associated with high-grade tumors and poor disease prognosis. Loss-of-function analysis in tumor cell lines indicated METTL1’s biological importance in cancer cell growth and survival. Functional annotation and pathway analysis of METTL1-associated proteins revealed that, in addition to the cofactor WDR4, RNA regulators and DNA packaging complexes may be functionally interconnected with METTL1 in human cancer. Our results provide new information for functional study of METTL alterations in human cancer and may lead to inhibitors that target cancer-promoting METTLs.
mRNA cap formation is a critical element in regulating mRNA function both in the nucleus and cytoplasm, and multiple mRNA capping genes have been associated with cancer. However, the role of the cap 2-O-metylation enzyme CMTR1 in cancer has not been significantly investigated. In Aim 2, we investigated CMTR1, finding that it is overexpressed at the RNA and protein level in multiple cancer types, as well as having significant survival effects. Using integrated genomic, transcriptomic, proteomic, and clinicopathological analyses, we find that CMTR1’s expression differs based on clinical subtype in multiple cancer types, and CMTR1’s post-translational modifications are also increased in tumor tissues. Using knockout and knockdown in vitro models, CMTR1 loss results in reduced 2-dimensional and anchorage-independent growth. RNA-seq showed that CMTR1 loss results in reduced expression of ribosomal protein and snoRNA host genes across multiple cell types. Since many of the downregulated genes are snoRNA hosts, we investigated if CMTR1 loss affects snoRNA levels; we find that CMTR1 loss reduced levels of selected snoRNAs. Together, these results suggest that CMTR1 is dysregulated in cancer and that further investigation of its suitability for targeting may be warranted.
Recommended Citation
Campeanu, Ion John, "Integrative Analysis Of Mettl And Cmtr1 Methyltransferases In Cancer" (2025). Wayne State University Dissertations. 4221.
https://digitalcommons.wayne.edu/oa_dissertations/4221