Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

RBM5 recruiting MGC32805 in a sandwich mode and inducing ΔFAS neoantigen and triggering FAS properties switch: implication in colorectal cancer

Oncogene volume 44, pages 3052–3069 (2025)Cite this article

Subjects

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.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The predominant splicing pattern of exon 6 skipping in FAS pre-mRNA is closely associated with elevated MGC32805 expression in CRC.
Fig. 2: Exon 6 skipping-induced ΔFAS isoform plays a critical role in the biological characteristics of CRC cells.
Fig. 3: AS factor RBM5 exhibits a positive correlation in expression with MGC32805 regulating disparate FAS isoforms in CRC.
Fig. 4: RBM5 maintains its splicing activity by specifically recruiting MGC32805 to inhibit E3 ligase-mediated protein degradation.
Fig. 5: RBM5 selectively recognizes the crucial motif in FAS pre-mRNA exon 6 to induce an AS-mediated neoantigen ΔFAS.
Fig. 6: RBM5 directly stabilized by MGC32805 targets the pre-mRNA to induce ΔFAS in a sandwich model in CRC.
Fig. 7: MGC32805/RBM5/FAS pre-mRNA drives FAS-AS events to mediate the CRC biological characteristics in vivo.
Fig. 8: RBM5 recruiting MGC32805 in a sandwich mode and inducing ΔFAS neoantigen and triggering FAS properties switch: Implication in colorectal cancer.

Similar content being viewed by others

Data availability

The authors declare that all the data supporting the findings in this study are available in this study and its Supplementary materials, or are available from the corresponding author through reasonable request.

References

  1. Cieply B, Carstens RP. Functional roles of alternative splicing factors in human disease. Wiley Interdiscip Rev RNA. 2015;6:311–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sterne-Weiler T, Weatheritt RJ, Best AJ, Ha KC, Blencowe BJ. Efficient and Accurate Quantitative Profiling of Alternative Splicing Patterns of Any Complexity on a Laptop. Mol Cell. 2018;72:187–200.e6.

    Article  CAS  PubMed  Google Scholar 

  3. Zhang X, Ameer FS, Azhar G, Wei JY. Alternative Splicing Increases Sirtuin Gene Family Diversity and Modulates Their Subcellular Localization and Function. Int J Mol Sci. 2021;22:473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jiang W, Chen L. Alternative splicing: Human disease and quantitative analysis from high-throughput sequencing. Comput Struct Biotechnol J. 2020;19:183–95.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bonnal SC, Lopez-Oreja I, Valcarcel J. Roles and mechanisms of alternative splicing in cancer - implications for care. Nat Rev Clin Oncol. 2020;17:457–74.

    Article  PubMed  Google Scholar 

  6. Lu SX, De Neef E, Thomas JD, Sabio E, Rousseau B, Gigoux M, et al. Pharmacologic modulation of RNA splicing enhances anti-tumor immunity. Cell. 2021;184:4032–47.e31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Stanley RF, Abdel-Wahab O. Dysregulation and therapeutic targeting of RNA splicing in cancer. Nat Cancer. 2022;3:536–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang Y, Qian J, Gu C, Yang Y. Alternative splicing and cancer: a systematic review. Signal Transduct Target Ther. 2021;6:78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ramesh P, Lannagan TR, Jackstadt R, Atencia Taboada L, Lansu N, Wirapati P, et al. BCL-XL is crucial for progression through the adenoma-to-carcinoma sequence of colorectal cancer. Cell Death Differ. 2021;28:3282–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Watanabe J, Kushihata F, Honda K, Sugita A, Tateishi N, Mominoki K, et al. Prognostic significance of Bcl-xL in human hepatocellular carcinoma. Surgery. 2004;135:604–12.

    Article  PubMed  Google Scholar 

  11. Karczmarek-Borowska B, Filip A, Wojcierowski J, Smolen A, Korobowicz E, Korszen-Pilecka I, et al. Estimation of prognostic value of Bcl-xL gene expression in non-small cell lung cancer. Lung Cancer. 2006;51:61–9.

    Article  PubMed  Google Scholar 

  12. Marone M, Scambia G, Mozzetti S, Ferrandina G, Iacovella S, De Pasqua A, et al. bcl-2, bax, bcl-XL, and bcl-XS expression in normal and neoplastic ovarian tissues. Clin Cancer Res. 1998;4:517–24.

    CAS  PubMed  Google Scholar 

  13. De Blasio A, Vento R, Di Fiore R. Mcl-1 targeting could be an intriguing perspective to cure cancer. J Cell Physiol. 2018;233:8482–98.

    Article  PubMed  Google Scholar 

  14. Wang H, Guo M, Wei H, Chen Y. Targeting MCL-1 in cancer: current status and perspectives. J Hematol Oncol. 2021;14:67.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Cheng J, Zhou T, Liu C, Shapiro JP, Brauer MJ, Kiefer MC, et al. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science. 1994;263:1759–62.

    Article  CAS  PubMed  Google Scholar 

  16. Huertas CS, Carrascosa LG, Bonnal S, Valcarcel J, Lechuga LM. Quantitative evaluation of alternatively spliced mRNA isoforms by label-free real-time plasmonic sensing. Biosens Bioelectron. 2016;78:118–25.

    Article  CAS  PubMed  Google Scholar 

  17. Du J, Luo Y, Zhang S, Wang B, Chen C, Zhu G, et al. Splicing factor SRSF1 promotes breast cancer progression via oncogenic splice switching of PTPMT1. J Exp Clin Cancer Res. 2021;40:171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen D, Zhao Z, Chen L, Li Q, Zou J, Liu S. PPM1G promotes the progression of hepatocellular carcinoma via phosphorylation regulation of alternative splicing protein SRSF3. Cell Death Dis. 2021;12:722.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Han P, Cao P, Yue J, Kong K, Hu S, Deng Y, et al. Knockdown of hnRNPA1 Promotes NSCLC Metastasis and EMT by Regulating Alternative Splicing of LAS1L exon 9. Front Oncol. 2022;12:837248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hamdollah Zadeh MA, Amin EM, Hoareau-Aveilla C, Domingo E, Symonds KE, Ye X, et al. Alternative splicing of TIA-1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance. Mol Oncol. 2015;9:167–78.

    Article  CAS  PubMed  Google Scholar 

  21. Gonzalez I, Munita R, Agirre E, Dittmer TA, Gysling K, Misteli T, et al. A lncRNA regulates alternative splicing via establishment of a splicing-specific chromatin signature. Nat Struct Mol Biol. 2015;22:370–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Khan MR, Wellinger RJ, Laurent B. Exploring the Alternative Splicing of Long Noncoding RNAs. Trends Genet. 2021;37:695–8.

    Article  CAS  PubMed  Google Scholar 

  23. Yadav B, Yadav P, Yadav S, Pandey AK. Role of long noncoding RNAs in the regulation of alternative splicing in glioblastoma. Drug Discov Today. 2024;29:104140.

    Article  CAS  PubMed  Google Scholar 

  24. Ouyang J, Zhong Y, Zhang Y, Yang L, Wu P, Hou X, et al. Long non-coding RNAs are involved in alternative splicing and promote cancer progression. Br J Cancer. 2022;126:1113–24.

    Article  CAS  PubMed  Google Scholar 

  25. Singh R, Gupta SC, Peng WX, Zhou N, Pochampally R, Atfi A, et al. Regulation of alternative splicing of Bcl-x by BC200 contributes to breast cancer pathogenesis. Cell Death Dis. 2016;7:e2262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Redis RS, Vela LE, Lu W, Ferreira de Oliveira J, Ivan C, Rodriguez-Aguayo C, et al. Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2. Mol Cell. 2016;61:520–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Inoue A, Yamamoto N, Kimura M, Nishio K, Yamane H, Nakajima K. RBM10 regulates alternative splicing. FEBS Lett. 2014;588:942–7.

    Article  CAS  PubMed  Google Scholar 

  28. Kotlajich MV, Hertel KJ. Death by splicing: tumor suppressor RBM5 freezes splice-site pairing. Mol Cell. 2008;32:162–4.

    Article  CAS  PubMed  Google Scholar 

  29. Mickleburgh I, Kafasla P, Cherny D, Llorian M, Curry S, Jackson RJ, et al. The organization of RNA contacts by PTB for regulation of FAS splicing. Nucleic Acids Res. 2014;42:8605–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wu H, Qin W, Lu S, Wang X, Zhang J, Sun T, et al. Long noncoding RNA ZFAS1 promoting small nucleolar RNA-mediated 2’-O-methylation via NOP58 recruitment in colorectal cancer. Mol Cancer. 2020;19:95.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lu S, Han L, Hu X, Sun T, Xu D, Li Y, et al. N6-methyladenosine reader IMP2 stabilizes the ZFAS1/OLA1 axis and activates the Warburg effect: implication in colorectal cancer. J Hematol Oncol. 2021;14:188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Julien P, Minana B, Baeza-Centurion P, Valcarcel J, Lehner B. The complete local genotype-phenotype landscape for the alternative splicing of a human exon. Nat Commun. 2016;7:11558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nakajima T, Ichii S, Furuyama J, Tamaoki T, Hashimoto T. A new alternative splice variant of the mouse Fas antigen with a deletion in the N-terminal portion of the extracellular domain. Life Sci. 1996;58:761–8.

    Article  CAS  PubMed  Google Scholar 

  34. Papoff G, Cascino I, Eramo A, Starace G, Lynch DH, Ruberti G. An N-terminal domain shared by Fas/Apo-1 (CD95) soluble variants prevents cell death in vitro. J Immunol. 1996;156:4622–30.

    Article  CAS  PubMed  Google Scholar 

  35. Sharma S, Carmona A, Skowronek A, Yu F, Collins MO, Naik S, et al. Apoptotic signalling targets the post-endocytic sorting machinery of the death receptor Fas/CD95. Nat Commun. 2019;10:3105.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Chen M, Manley JL. Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat Rev Mol Cell Biol. 2009;10:741–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, et al. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell. 2010;39:925–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang Y, Fang Y, Ma L, Xu J, Lv C, Deng L, et al. LINC00857 regulated by ZNF460 enhances the expression of CLDN12 by sponging miR-150-5p and recruiting SRSF1 for alternative splicing to promote epithelial-mesenchymal transformation of pancreatic adenocarcinoma cells. RNA Biol. 2022;19:548–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhu LY, Zhu YR, Dai DJ, Wang X, Jin HC. Epigenetic regulation of alternative splicing. Am J Cancer Res. 2018;8:2346–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. He S, Shi J, Zhou H, Li Q, Wu L. Lnc-ABCA12-8 confers acquired resistance to gefitinib in non-small cell lung cancer by regulating the alternative splicing of fibronectin 1 in the IIICS region. Cancer Gene Ther. 2022;29:1686–96.

    Article  CAS  PubMed  Google Scholar 

  41. Liu M, Zhang S, Zhou H, Hu X, Li J, Fu B, et al. The interplay between non-coding RNAs and alternative splicing: from regulatory mechanism to therapeutic implications in cancer. Theranostics. 2023;13:2616–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Du JX, Zhu GQ, Cai JL, Wang B, Luo YH, Chen C, et al. Splicing factors: Insights into their regulatory network in alternative splicing in cancer. Cancer Lett. 2021;501:83–104.

    Article  CAS  PubMed  Google Scholar 

  43. Sutherland LC, Wang K, Robinson AG. RBM5 as a putative tumor suppressor gene for lung cancer. J Thorac Oncol. 2010;5:294–8.

    Article  PubMed  Google Scholar 

  44. Rintala-Maki ND, Goard CA, Langdon CE, Wall VE, Traulsen KE, Morin CD, et al. Expression of RBM5-related factors in primary breast tissue. J Cell Biochem. 2007;100:1440–58.

    Article  CAS  PubMed  Google Scholar 

  45. Bradley RK, Anczukow O. RNA splicing dysregulation and the hallmarks of cancer. Nat Rev Cancer. 2023;23:135–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang E, Aifantis I. RNA Splicing and Cancer. Trends Cancer. 2020;6:631–44.

    Article  CAS  PubMed  Google Scholar 

  47. Zhang L, Zhang Q, Yang Y, Wu C. The RNA recognition motif domains of RBM5 are required for RNA binding and cancer cell proliferation inhibition. Biochem Biophys Res Commun. 2014;444:445–50.

    Article  CAS  PubMed  Google Scholar 

  48. Serrano P, Hammond JA, Geralt M, Wuthrich K. Splicing Site Recognition by Synergy of Three Domains in Splicing Factor RBM10. Biochemistry. 2018;57:1563–7.

    Article  CAS  PubMed  Google Scholar 

  49. Chang J, Zhang Y, Zhou T, Qiao Q, Shan J, Chen Y, et al. RBM10 C761Y mutation induced oncogenic ASPM isoforms and regulated β-catenin signaling in cholangiocarcinoma. J Exp Clin Cancer Res. 2024;43:104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Corsini L, Bonnal S, Basquin J, Hothorn M, Scheffzek K, Valcarcel J, et al. U2AF-homology motif interactions are required for alternative splicing regulation by SPF45. Nat Struct Mol Biol. 2007;14:620–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We gratefully appreciate the efforts and contributions of doctors, and technical staff at the First Hospital of China Medical University. We thanks Shanghai OE Biotech Technology Co, Ltd. for microarray sequencing service and bioinformatics support. This work was supported by grants from the National Natural Science Foundation of China (82272915, 82073884), China Postdoctoral Science Foundation (2023MD734246), the project of the fourth batch of science and technology plan of Liaoning province (2021JH210300133), science and technology innovation team project of China Medical University (CXTD2022007), supporting the high-quality development of science and technology funding projects at China Medical University (2022011963-JH2/202), Liaoning Province Central Guide Local Science and Technology Development Fund (2024JH6/100800003), and Beijing CSCO Clinical Oncology Research Foundation (Y-Gilead2024-PT-0201).

Author information

Author notes

  1. These authors contributed equally: Huizhe Wu, Xiaoyun Hu, Yilin Wang, Xianglong Zhu

Authors and Affiliations

  1. Scientific experimental center, School of Pharmacy, China Medical University, Shenyang, 110122, PR China

    Huizhe Wu & Xiaoyun Hu

  2. Liaoning Key Laboratory of molecular targeted anti-tumor drug development and evaluation, Liaoning Cancer immune peptide drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, 110122, PR China

    Huizhe Wu, Xiaoyun Hu & Minjie Wei

  3. Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, PR China

    Yilin Wang, Xianglong Zhu, Qing Zhao, Yingqi Zhao, Wanlin Cui, Mingrong Zhang, Haishan Zhao & Minjie Wei

  4. Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, 110001, PR China

    Kai Li

Authors
  1. Huizhe Wu
    View author publications

    Search author on:PubMed Google Scholar

  2. Xiaoyun Hu
    View author publications

    Search author on:PubMed Google Scholar

  3. Yilin Wang
    View author publications

    Search author on:PubMed Google Scholar

  4. Xianglong Zhu
    View author publications

    Search author on:PubMed Google Scholar

  5. Qing Zhao
    View author publications

    Search author on:PubMed Google Scholar

  6. Yingqi Zhao
    View author publications

    Search author on:PubMed Google Scholar

  7. Wanlin Cui
    View author publications

    Search author on:PubMed Google Scholar

  8. Mingrong Zhang
    View author publications

    Search author on:PubMed Google Scholar

  9. Haishan Zhao
    View author publications

    Search author on:PubMed Google Scholar

  10. Kai Li
    View author publications

    Search author on:PubMed Google Scholar

  11. Minjie Wei
    View author publications

    Search author on:PubMed Google Scholar

Contributions

MW, KL, and HW conceived and designed the project; XH, YW, XZ, QZ, YZ, WC, and MZ performed experiments and/or data acquisition and analyses; MW, KL, HW, XH, and HZ contributed technical/reagents materials, analytic tools and/or grant support; MW, HW, and XH prepared, wrote, and/or revision the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Kai Li or Minjie Wei.

Ethics declarations

Competing interests

The authors declare no competing interests.

Consent for publication

All of the authors have written informed consent.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, H., Hu, X., Wang, Y. et al. RBM5 recruiting MGC32805 in a sandwich mode and inducing ΔFAS neoantigen and triggering FAS properties switch: implication in colorectal cancer. Oncogene 44, 3052–3069 (2025). https://doi.org/10.1038/s41388-025-03390-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41388-025-03390-4

Search

Advanced search

Quick links