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RBM5 recruiting MGC32805 in a sandwich mode and inducing ΔFAS neoantigen and triggering FAS properties switch:
Huizhe Wu1,2, Xiaoyun Hu1,2, Yilin Wang3
1Scientific experimental center, School of Pharmacy, China Medical University, Shenyang, 110122, PR China.
Abstract:
Pre-mRNA alternative splicing (AS) is a crucial process, which plays a significant role in inducing tumor subtype-specific alterations and the hallmark of epigenetic heterogeneity in tumorigenesis. However, the regulatory mechanisms of pre-mRNA AS remain obscure. This study demonstrates that splicing factor RBM5 recruits long non-coding RNA MGC32805, and they act in concert as oncogenes in colorectal cancer (CRC) cells by preventing apoptosis, as well as promoting migration and resistance to 5-Fluorouracil (5-FU). Specifically, they promote the exclusion of exon 6 in the FAS pre-mRNA, leading to decreased expression of mFAS (an apoptotic isoform) and increased expression of ΔFAS (an anti-apoptotic isoform) in both CRC cells and a mouse xenograft model. RBM5, which contains Leu650 and Arg681 residues in the ZnF-C2H2 domain, recognizes the "GUACG" (-1299 to -1303) motif in MGC32805. Furthermore, MGC32805 blocks the binding site (Lys645) of the E3 ubiquitin ligase PRPF19, which targets RBM5 for degradation, thus increasing the stability of RBM5. The His665 and Leu668 residues of RBM5 specifically bind to the FAS exon 6 adjacent element (GAACAAA), which drives FAS-AS events and increases the expression ratio of the ΔFAS/mFAS isoforms. These findings introduce a novel research strategy to investigate the epigenetic heterogeneity and plasticity of tumorigenesis. They also shed light on the mechanism of MGC32805-mediated transformation of the FAS tumor neoantigen function from a tumor suppressor to an oncogene at the AS level through its interactions with RBM5.
Insights
Splicing factor RBM5 and long non-coding RNA MGC32805 cooperate as oncogenes in colorectal cancer, promoting tumor growth and 5-FU resistance by altering FAS pre-mRNA splicing.
Area of Science:
- Molecular Biology
- Cancer Research
- Epigenetics
Background:
- Pre-mRNA alternative splicing (AS) is critical in tumorigenesis and epigenetic heterogeneity.
- Regulatory mechanisms of AS in cancer remain largely unknown.
- Understanding AS is key to novel cancer therapies.
Purpose of the Study:
- To elucidate the regulatory mechanisms of pre-mRNA AS in colorectal cancer (CRC).
- To investigate the oncogenic roles of splicing factor RBM5 and long non-coding RNA MGC32805 in CRC.
- To identify novel therapeutic targets for CRC.
Main Methods:
- Investigated the interaction between RBM5 and MGC32805 in CRC cells and a mouse xenograft model.
- Analyzed the effect of RBM5-MGC32805 complex on FAS pre-mRNA splicing.
- Determined the molecular mechanisms underlying RBM5 stabilization and FAS AS regulation.
Main Results:
- RBM5 and MGC32805 act as oncogenes in CRC, promoting cell migration, anti-apoptosis, and 5-FU resistance.
- They induce exclusion of exon 6 in FAS pre-mRNA, increasing anti-apoptotic ΔFAS and decreasing apoptotic mFAS isoforms.
- MGC32805 stabilizes RBM5 by blocking PRPF19-mediated degradation, and RBM5 directly binds to FAS pre-mRNA to drive AS.
Conclusions:
- RBM5 and MGC32805 form a novel oncogenic complex in CRC.
- This complex alters FAS splicing, shifting its function from tumor suppressor to oncogene.
- Findings provide new insights into epigenetic heterogeneity and potential therapeutic strategies for CRC.
