RNA Methyltransferase FTSJ3 Regulates Ribosome Biogenesis in Liver Cancer: Molecular Mechanisms and Therapeutic Potential
Abstract
Liver cancer is a devastating disease that affects millions of men and women worldwide. The incidence of liver cancer is increasing in the United States, especially among military personnel and Veterans. Each year in the United States, about 24,500 men and 10,000 women get liver cancer, and about 18,600 men and 9,000 women die from this disease. Among the main risk factors for liver cancer are hepatitis B and C infection, alcohol consumption, obesity, and male gender, all of which are over-represented in the U.S. military and Veteran communities. Currently, less than 20% of patients with liver cancer are responsive to curative therapies, and most are treated with systemic and/or locoregional therapies that only extend survival by months, not years. Thus, there are significant needs to develop new classes of molecules that target its unexplored cellular mechanisms to fight this devastating disease. Our research focuses on identifying key oncogenic factors that drive the progression of different subtypes of human cancers and then testing the effects of new anticancer agents. RNA serves as a connecting link by which genetic information passes from DNA to protein. There are many chemical changes to RNA nucleotides – known as RNA modifications – that regulate the structure, stability, translation, and function of almost every major class of human RNA. Notably, RNA modification enzymes have emerged as promising molecular targets for anti-cancer drug development. By integrated analysis of genomics/proteomics and clinical data of The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we discovered one of the RNA modification enzymes, called FTSJ3 (FtsJ RNA 2 -O-methyltransferase 3), is dramatically up-regulated in a set of liver cancer samples, and significantly associated with high-grade tumors and poor disease prognosis in liver cancer patients. Metagenomic analysis of TCGA dataset revealed that the FTSJ3 gene is gained/amplified in 35.2% of liver cancer. Our preliminary studies uncovered that knockdown of FTSJ3 inhibits liver cancer cell growth in vitro. Additionally, FTSJ3 enzymatic domain had specific motifs and showed inhibitory active site architecture. Furthermore, FTSJ3 protein is predominantly localized at the nucleolus, the primary site of rRNA processing and ribosome biogenesis. Ribosomes are the molecular machines that produce all cellular proteins through a complex and highly regulated biochemical process called translation. Strong upregulation of ribosome biogenesis is an important molecular alteration of rapidly dividing liver cancer cells, owing to the high demand for ribosomes and protein translation. All these findings make the FTSJ3 an attractive target for the treatment of liver cancer. The objectives of this application are: (1) elucidate the biological roles and molecular mechanisms by which RNA modification enzyme FTSJ3 promotes liver tumorigenesis, and (2) explore the therapeutic potential of targeting FTSJ3 in a set of FTSJ3-amplified/overexpressed liver cancer. The first Specific Aim will define the functional significance of FTSJ3 and the therapeutic potential of targeting FTSJ3 in liver cancer in culture cells and animal models. We will use genetic approaches and/or small-molecule compounds to measure the effects of inhibiting FTSJ3 on blocking aggressive phenotypes of liver cancer cells in vitro. We will then determine the impact of inhibiting FTSJ3 function on the tumor growth of liver cancer in mouse models. In Specific Aim 2, we will determine the functional role and molecular mechanism by which FTSJ3 alters RNA modification patterns, ribosome biogenesis, and translational capacity, subsequently supporting liver tumorigenesis. We will examine how FTSJ3 recognizes a combined sequence and structural feature of targeted RNA in liver cancer cells. We will define the functional roles of FTSJ3 on RNA modification abundance, Ras-like GTPase (G
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310620
Entities
People
- Zeng-quan Yang
Organizations
- United States Army
- Wayne State University