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:

Pan-cancer oncogenic properties and therapeutic potential of SF3B4

Cancer Gene Therapy volume 32, pages 706–720 (2025)Cite this article

Subjects

Abstract

Splicing factor 3B (SF3B) subunit 4 (SF3B4), an SF3B complex component essential for spliceosome assembly and accurate splicing, plays a major role in cancer development. However, the precise mechanism through which SF3B4 contributes to tumor growth remains unclear. Here, we demonstrate that SF3B4 is strongly expressed in patients with various cancer types and correlated with their survival. By using hepatocellular carcinoma (HCC) as a model, we reveal that SF3B4’s interactions with and regulatory influence on the checkpoint protein BUB1 are essential for appropriate cancer cell mitosis and proliferation. Our results thus demonstrate the roles of SF3B4 as both a cell-cycle regulator and an oncogenic factor in HCC, highlighting its potential as a pan-cancer therapeutic target and diagnostic biomarker.

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: Comparison of SF3B4 expression between tumor and paracancerous normal tissues.
Fig. 2: Association of SF3B4 expression with OS, DSS, and ROC curves.
Fig. 3: Gene alteration and RNA modification analysis of SF3B4.
Fig. 4: Roles of SF3B4 in pan-cancer functional status.
Fig. 5: Oncogenic roles of SF3B4 in HCC.
Fig. 6: Regulatory role of SF3B4 in proliferation and cell-cycle progression of HCC cells.
Fig. 7: Modulation of the checkpoint protein BUB1 expression by SF3B4 in the cell cycle.

Similar content being viewed by others

Data availability

The datasets used in this study are available from the corresponding author upon reasonable request. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD052853.

References

  1. The global challenge of cancer. Nat Cancer. 2020;1:1–2.

  2. Lancet Public The. H. Inequalities in cancer: a major public health concern. Lancet Public Health. 2024;9:e147.

    Article  Google Scholar 

  3. He S, Xia C, Li H, Cao M, Yang F, Yan X, et al. Cancer profiles in China and comparisons with the USA:a comprehensive analysis in the incidence,mortality,survival,staging,and attribution to risk factors. Science China. 2024;67:122–31.

  4. Ding R, Yu X, Hu Z, Dong Y, Huang H, Zhang Y, et al. Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells. Immunity. 2024;57:528–40.e6.

    Article  CAS  PubMed  Google Scholar 

  5. Wahl MC, Will CL, Luhrmann R. The spliceosome: design principles of a dynamic RNP machine. Cell. 2009;136:701–18.

    Article  CAS  PubMed  Google Scholar 

  6. Mm G, Sander B, Cl W, Luhrmann R, Stark H. Molecular Architecture of the Multiprotein Splicing Factor SF3b. Science. 2003;300:980–84.

    Article  Google Scholar 

  7. Bland P, Saville H, Wai PT, Curnow L, Muirhead G, Nieminuszczy J, et al. SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response. Nat Genet. 2023;55:1311–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dvinge H, Kim E, Abdel-Wahab O, Bradley RK. RNA splicing factors as oncoproteins and tumour suppressors. Nature Rev Cancer. 2016;16:413–30.

    Article  CAS  Google Scholar 

  9. O’Connor CM, Narla G. Splice of Life for Cancer: Missplicing of PPP2R5A by Mutant SF3B1 Leads to MYC Stabilization and Tumorigenesis. Cancer Discov. 2020;10:765–67.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Patnaik MM. How I diagnose and treat chronic myelomonocytic leukemia. Haematologica. 2022;107:1503–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang S, Liu Y, Xiao H, Chen Z, Yang X, Yin J, et al. Inhibition of SF3B1 improves the immune microenvironment through pyroptosis and synergizes with alphaPDL1 in ovarian cancer. Cell Death Dis. 2023;14:775.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gangat N, Patnaik MM, Tefferi A. Myelodysplastic syndromes: Contemporary review and how we treat. Am J Hematol. 2016;91:76–89.

    Article  CAS  PubMed  Google Scholar 

  13. Steensma DP, Wermke M, Klimek VM, Greenberg PL, Platzbecker U. Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms. Leukemia. 2021;35:3542–50.

  14. Sciarrillo R, Wojtuszkiewicz A, Assaraf YG, Jansen G, Kaspers GJL, Giovannetti E, et al. The role of alternative splicing in cancer: From oncogenesis to drug resistance. Drug Resist Updat. 2020;53:100728.

    Article  PubMed  Google Scholar 

  15. Wang SJ, Dougan SK, Dougan M. Immune mechanisms of toxicity from checkpoint inhibitors. Trends cancer. 2023;9:543–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Larsen NA. The SF3b Complex is an Integral Component of the Spliceosome and Targeted by Natural Product-Based Inhibitors. Subcell Biochem. 2021;96:409–32.

    Article  CAS  PubMed  Google Scholar 

  17. Champion-Arnaud P, Reed R. The prespliceosome components SAP 49 and SAP 145 interact in a complex implicated in tethering U2 snRNP to the branch site. Genes Dev. 1994;8:1974–83.

    Article  CAS  PubMed  Google Scholar 

  18. Bernier FP, Caluseriu O, Ng S, Schwartzentruber J, Buckingham KJ, Innes AM, et al. Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome. Am J Hum Genet. 2012;90:925–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Diao Y, Li Y, Wang Z, Wang S, Li P, Kong B. SF3B4 promotes ovarian cancer progression by regulating alternative splicing of RAD52. Cell Death Dis. 2022;13:179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li Y, Diao Y, Wang Z, Wang S, Peng J, Kong B. The splicing factor SF3B4 drives proliferation and invasion in cervical cancer by regulating SPAG5. Cell Death Discov. 2022;8:326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liu Z, Li W, Pang Y, Zhou Z, Liu S, Cheng K, et al. SF3B4 is regulated by microRNA-133b and promotes cell proliferation and metastasis in hepatocellular carcinoma. EBioMedicine. 2018;38:57–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Han C, Chen J, Huang J, Zhu R, Zeng J, Yu H, et al. Single-cell transcriptome analysis reveals the metabolic changes and the prognostic value of malignant hepatocyte subpopulations and predict new therapeutic agents for hepatocellular carcinoma. Front Oncol. 2023;13:1104262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shen Q, Nam SW. SF3B4 as an early-stage diagnostic marker and driver of hepatocellular carcinoma. BMB Rep. 2018;51:57–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Caicedo HH, Hashimoto DA, Caicedo JC, Pentland A, Pisano GP. Visualizing and interpreting cancer genomics data via the Xena platform. Nature Biotechnol. 2020;38:669–73.

    Article  CAS  Google Scholar 

  25. Vasaikar SV, Straub P, Wang J, Zhang B. LinkedOmics: analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res. 2018;46:D956–D63.

    Article  CAS  PubMed  Google Scholar 

  26. Thul PJ, Åkesson L, Wiking M, Mahdessian D, Geladaki A, Ait Blal H, et al. A subcellular map of the human proteome. Science. 2017; 356:eaal3321.

  27. Yuan H, Yan M, Zhang G, Liu W, Deng C, Liao G, et al. CancerSEA: a cancer single-cell state atlas. Nucleic Acids Res. 2019;47:D900–D08.

    Article  CAS  PubMed  Google Scholar 

  28. Shen W, Song Z, Zhong X, Huang M, Shen D, Gao P, et al. Sangerbox: A comprehensive, interaction-friendly clinical bioinformatics analysis platform. Imeta. 2022;1:e36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.

    Article  PubMed  Google Scholar 

  32. Pan Q, Luo P, Shi C. PC4-mediated Ku complex PARylation facilitates NHEJ-dependent DNA damage repair. J Biol Chem. 2023;299:105032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Barbieri I, Kouzarides T. Role of RNA modifications in cancer. Nat Rev Cancer. 2020;20:303–22.

    Article  CAS  PubMed  Google Scholar 

  34. Li X, Ma S, Deng Y, Yi P, Yu J. Targeting the RNA m(6)A modification for cancer immunotherapy. Mol Cancer. 2022;21:76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu X, Du Y, Huang Z, Qin H, Chen J, Zhao Y. Insights into roles of METTL14 in tumors. Cell Prolif. 2022;55:e13168.

    Article  CAS  PubMed  Google Scholar 

  36. Global cancer burden growing, amidst mounting need for services. Saudi Medical Journal. 2024; 45:326–7.

  37. Chidambaranathan-Reghupaty S, Fisher PB, Sarkar D. Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification. Adv Cancer Res. 2021;149:1–61.

    Article  CAS  PubMed  Google Scholar 

  38. Singal AG, Kanwal F, Llovet JM. Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy. Nat Rev Clin Oncol. 2023;20:864–84.

    Article  Google Scholar 

  39. Llovet JM, Pinyol R, Kelley RK, El-Khoueiry A, Reeves HL, Wang XW, et al. Molecular pathogenesis and systemic therapies for hepatocellular carcinoma. Nat Cancer. 2022;3:386–401.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Plaks V, Kong N, Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells?. Cell Stem Cell. 2015;16:225–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kreso A, O’Brien CA, van Galen P, Gan OI, Notta F, Brown AM, et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science. 2013;339:543–8.

    Article  CAS  PubMed  Google Scholar 

  42. Fischer M, Schade AE, Branigan TB, Müller GA, DeCaprio JA. Coordinating gene expression during the cell cycle. Trends Biochemical Sci. 2022;47:1009–22.

    Article  CAS  Google Scholar 

  43. Gallo D, Young JTF, Fourtounis J, Martino G, Álvarez-Quilón A, Bernier C, et al. CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition. Nature. 2022;604:749–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sher G, Masoodi T, Patil K, Akhtar S, Kuttikrishnan S, Ahmad A, et al. Dysregulated FOXM1 signaling in the regulation of cancer stem cells. Semin Cancer Biol. 2022;86:107–21.

    Article  CAS  PubMed  Google Scholar 

  45. Elowe S, Bolanos-Garcia VM. The spindle checkpoint proteins BUB1 and BUBR1: (SLiM)ming down to the basics. Trends Biochemical Sci. 2022;47:352–66.

    Article  CAS  Google Scholar 

  46. Singh P, Pesenti ME, Maffini S, Carmignani S, Hedtfeld M, Petrovic A, et al. BUB1 and CENP-U, Primed by CDK1, Are the Main PLK1 Kinetochore Receptors in Mitosis. Mol Cell. 2021;81:67–87.e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wang X, Babu JR, Harden JM, Jablonski SA, Gazi MH, Lingle WL, et al. The Mitotic Checkpoint Protein hBUB3 and the mRNA Export Factor hRAE1 Interact with GLE2p-binding Sequence (GLEBS)-containing Proteins*. J Biol Chem. 2001;276:26559–67.

    Article  CAS  PubMed  Google Scholar 

  48. Taylor SS, Ha E, McKeon F. The human homologue of Bub3 is required for kinetochore localization of Bub1 and a Mad3/Bub1-related protein kinase. J Cell Biol. 1998;142:1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ding J, Li C, Cheng Y, Du Z, Wang Q, Tang Z, et al. Alterations of RNA splicing patterns in esophagus squamous cell carcinoma. Cell Biosci. 2021;11:36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. He G, Gu K, Wei J, Zhang J. METTL3-mediated the m6A modification of SF3B4 facilitates the development of non-small cell lung cancer by enhancing LSM4 expression. Thorac Cancer. 2024;15:919–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Iguchi T, Masuda T, Nambara S, Kidogami S, Ogawa Y, Hu Q, et al. Increased Copy Number of the Gene Encoding SF3B4 Indicates Poor Prognosis in Hepatocellular Carcinoma. Anticancer Res. 2016;36:2139–44.

    CAS  PubMed  Google Scholar 

  52. 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 

  53. Venkataramany AS, Schieffer KM, Lee K, Cottrell CE, Wang PY, Mardis ER, et al. Alternative RNA splicing defects in pediatric cancers: new insights in tumorigenesis and potential therapeutic vulnerabilities. Ann Oncol. 2022;33:578–92.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Professor Shi Chunmeng from the Affiliated Hospital of the Third Military Medical University for his discussion regarding the manuscript. Mass spectrometry analysis was performed by the Bioinformatics and Omics Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University.

Funding

This work was supported by grants from the National Natural Science Foundation of China [grant numbers 82373023, 82273033, 82072924]; the Guangdong Science and Technology Department [grant number 2022B1515020100]; and the Guangzhou Bureau of Science and Technology [grant number 202201020575, 2024A04J4691].

Author information

Author notes

  1. These authors contributed equally: Yanmei Shi, Qimei Pan, Wenli Chen.

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China

    Yanmei Shi, Qimei Pan, Limin Xie, Shiru Tang, Zhizhi Yang, Man Zhang, Dong Yin, Lehang Lin & Jian-You Liao

  2. Center for Bioresources and Drug Discovery and School of Biosciences and Biopharmaceutics, Guangdong Province Key Laboratory for Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China

    Wenli Chen

Authors
  1. Yanmei Shi
    View author publications

    Search author on:PubMed Google Scholar

  2. Qimei Pan
    View author publications

    Search author on:PubMed Google Scholar

  3. Wenli Chen
    View author publications

    Search author on:PubMed Google Scholar

  4. Limin Xie
    View author publications

    Search author on:PubMed Google Scholar

  5. Shiru Tang
    View author publications

    Search author on:PubMed Google Scholar

  6. Zhizhi Yang
    View author publications

    Search author on:PubMed Google Scholar

  7. Man Zhang
    View author publications

    Search author on:PubMed Google Scholar

  8. Dong Yin
    View author publications

    Search author on:PubMed Google Scholar

  9. Lehang Lin
    View author publications

    Search author on:PubMed Google Scholar

  10. Jian-You Liao
    View author publications

    Search author on:PubMed Google Scholar

Contributions

The conceptualization and writing of this manuscript were performed by YS and QP. The methodology was designed and implemented by YS, QP, and WC. Data validation and quality control were conducted by LX. Specimen collection and processing were carried out by ST. Literature review and comprehensive analysis were completed by ZY and MZ. Manuscript revision and supervised were performed by DY, LL and JL.

Corresponding authors

Correspondence to Lehang Lin or Jian-You Liao.

Ethics declarations

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethics approval and consent to participate

All methods in this study were performed in accordance with the relevant guidelines and regulations. Ethical approval for this study was obtained from the Sun Yat-sen Memorial Hospital, Sun Yat-Sen University and adhered to the principles of the Declaration of Helsink. Approval No. SYSKY-2023-010-01. Informed consent was obtained from all human participants prior to their inclusion in the study.

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

Shi, Y., Pan, Q., Chen, W. et al. Pan-cancer oncogenic properties and therapeutic potential of SF3B4. Cancer Gene Ther 32, 706–720 (2025). https://doi.org/10.1038/s41417-025-00910-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41417-025-00910-y

Search

Advanced search

Quick links