Abstract 5569: FBXW7 functional loss enhances IGF2BP1 levels, implicating oncogenic m6A RNA modification dynamics in colon cancer

Abstract FBXW7 is an E3 ubiquitin ligase and known as a tumor suppressor gene. Considering the high mutation frequency of FBXW7 observed in colon cancer mutation profiling, it is important to identify the interactive partners of FBXW7 for developing effective colon cancer treatments. Many reports have demonstrated diverse changes in cancer development and progression under FBXW7 mutant conditions at transcriptomic and proteomics levels. However, it is unclear how post-transcriptional modifications, especially RNA modifications, are affected under FBXW7 mutant conditions. To find the candidate targets of FBXW7 in protein level, we performed LC-MS analysis under conditions of FBXW7 functional loss. We analyzed gene ontology biological pathway (GOBP) enrichment analysis with up-regulated genes and found gene terms associated with RNA metabolism (such as mRNA metabolic process, positive regulation of 3’-UTR-mediated mRNA stabilization and mRNA transport). As the RNA metabolism is influenced by various types of RNA modifications, we focused on N6-methyladenosine (m6A) RNA methylation, a prevalent and significant post-transcriptional modification that plays a crucial role in regulating various RNA functions in eukaryotic messenger RNAs. To validate the LC-MS analysis, we profiled m6A regulators (writer, eraser and reader groups) in protein and mRNA level in FBXW7 knock-out and transient knock-down cells. The protein level of IGF2BP1, which belongs to m6A reader proteins, was up-regulated in both FBXW7 knock-out and knock-down conditions, but not in mRNA level. Additionally, the expression of IGF2BP1 increased compared to normal tissue, and expression of IGF2BP1 was associated with decreased survival rates, suggesting that IGF2BP1 plays an oncogenic role, as indicated by the TCGA colon cancer database. Our study suggests that IGF2BP1 is a crucial target in FBXW7 mutant colon cancer. Citation Format: Soo-Jin Lee, Sung-Yup Cho. FBXW7 functional loss enhances IGF2BP1 levels, implicating oncogenic m6A RNA modification dynamics in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5569.