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:

Identification of HDAC4 as a potential therapeutic target and prognostic biomarker for ZFTA-fused ependymomas

Cancer Gene Therapy volume 30, pages 1105–1113 (2023)Cite this article

Subjects

Abstract

Members of the HDAC family are predictive biomarkers and regulate the tumorigenesis in several cancers. However, the role of these genes in the biology of intracranial ependymomas (EPNs) remains unexplored. Here, an analysis of eighteen HDACs genes in an EPN transcriptomic dataset, revealed significantly higher levels of HDAC4 in supratentorial ZFTA fusion (ST-ZFTA) compared with ST-YAP1 fusion and posterior fossa EPNs, while HDAC7 and SIRT2 were downregulated in ST-ZFTA. HDAC4 was also overexpressed in ST-ZFTA as measured by single-cell RNA-Seq, quantitative real time-polymerase chain reaction, and immunohistochemistry. Survival analyses showed a significantly worse outcome for EPNs with higher HDAC4 and SIRT1 mRNA levels. Ontology enrichment analysis showed an HDAC4-high signature consistent with viral processes while collagen-containing extracellular matrix and cell-cell junction were enriched in those with an HDAC4-low signature. Immune gene analysis demonstrated a correlation between HDAC4 expression and low levels of NK resting cells. Several small molecules compounds targeting HDAC4 and ABCG2, were predicted by in silico analysis to be effective against HDAC4-high ZFTA. Our results provide novel insights into the biology of the HDAC family in intracranial ependymomas and reveal HDAC4 as a prognostic marker and potential therapeutic target in ST-ZFTA.

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: mRNA expression of the HDAC family in intracranial ependymomas.
Fig. 2: HDAC4 is overexpressed in ST-ZFTA.
Fig. 3: High levels of HDAC4 in ST-ZFTA using Brazilian cohort.
Fig. 4: Prognostic value of HDAC4 in ST-ZFTA tumors.
Fig. 5: Identification of the DEGs between HDAC4-high and HDAC4-low.

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request.

References

  1. Ostrom QT, Patil N, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2013–2017. Neuro-Oncol. 2020;22:iv1–iv96.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ellison DW, Aldape KD, Capper D, Fouladi M, Gilbert MR, Gilbertson RJ, et al. cIMPACT‐NOW update 7: advancing the molecular classification of ependymal tumors. Brain Pathol. 2020;30:863–6.

    PubMed  PubMed Central  Google Scholar 

  3. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-Oncol. 2021;23:1231–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Arabzade A, Zhao Y, Varadharajan S, Chen H-C, Jessa S, Rivas B, et al. ZFTA–RELA dictates oncogenic transcriptional programs to drive aggressive supratentorial ependymoma. Cancer Discov. 2021;11:2200–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zheng T, Ghasemi DR, Okonechnikov K, Korshunov A, Sill M, Maass KK, et al. Cross-species genomics reveals oncogenic dependencies in ZFTA/C11orf95 fusion–positive supratentorial ependymomas. Cancer Discov. 2021;11:2230–47.

    Article  CAS  PubMed  Google Scholar 

  6. Andreiuolo F, Varlet P, Tauziède-Espariat A, Jünger ST, Dörner E, Dreschmann V, et al. Childhood supratentorial ependymomas with YAP1-MAMLD1 fusion: an entity with characteristic clinical, radiological, cytogenetic and histopathological features. Brain Pathol. 2019;29:205–16.

    Article  CAS  PubMed  Google Scholar 

  7. Chinnam D, Gupta K, Kiran T, Saraswati A, Salunke P, Madan R, et al. Molecular subgrouping of ependymoma across three anatomic sites and their prognostic implications. Brain Tumor Pathol. 2022;39:151–61.

    Article  CAS  PubMed  Google Scholar 

  8. Kresbach C, Neyazi S, Schüller U. Updates in the classification of ependymal neoplasms: The 2021 WHO Classification and beyond. Brain Pathol. 2022;32:e13068.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Zaytseva M, Papusha L, Novichkova G, Druy A. Molecular stratification of childhood ependymomas as a basis for personalized diagnostics and treatment. Cancers. 2021;13:4954–4954.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Li Y, Seto E. HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb Perspect Med. 2016;6:a026831–a026831.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Li G, Tian Y, Zhu W-G. The roles of histone deacetylases and their inhibitors in cancer therapy. Front Cell Dev Biol. 2020;8:576946.

  12. Milde T, Kleber S, Korshunov A, Witt H, Hielscher T, Koch P, et al. A novel human high-risk ependymoma stem cell model reveals the differentiation-inducing potential of the histone deacetylase inhibitor Vorinostat. Acta Neuropathol. 2011;122:637–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Antonelli R, Jiménez C, Riley M, Servidei T, Riccardi R, Soriano A, et al. CN133, a novel brain-penetrating histone deacetylase inhibitor, hampers tumor growth in patient-derived pediatric posterior fossa ependymoma models. Cancers. 2020;12:1922–1922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pajtler KW, Witt H, Sill M, Jones DTW, Hovestadt V, Kratochwil F, et al. Molecular classification of ependymal tumors across All CNS compartments, histopathological grades, and age groups. Cancer Cell. 2015;27:728–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics. 2016;32:2847–9.

    Article  CAS  PubMed  Google Scholar 

  16. Gillen AE, Riemondy KA, Amani V, Griesinger AM, Gilani A, Venkataraman S, et al. Single-Cell RNA sequencing of childhood ependymoma reveals neoplastic cell subpopulations that impact molecular classification and etiology. Cell Rep. 2020;32:108023–108023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. de Sousa GR, Lira RCP, de Almeida Magalhães T, da Silva KR, Nagano LFP, Saggioro FP, et al. A coordinated approach for the assessment of molecular subgroups in pediatric ependymomas using low-cost methods. J Mol Med. 2021;99:1101–1113.

  18. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nat Protoc. 2008;3:1101–8.

    Article  CAS  PubMed  Google Scholar 

  19. Wen Y, Zhang X, Li X, Tian L, Shen S, Ma J, et al. Histone deacetylase (HDAC) 11 inhibits matrix metalloproteinase (MMP) 3 expression to suppress colorectal cancer metastasis. J Cancer. 2022;13:1923–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10:1523–1523.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ, et al. The connectivity map: using gene-expression signatures to connect small molecules, genes, and disease. Science. 2006;313:1929–35.

    Article  CAS  PubMed  Google Scholar 

  22. 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 

  23. Merchant TE, Bendel AE, Sabin ND, Burger PC, Shaw DW, Chang E, et al. Conformal radiation therapy for pediatric ependymoma, chemotherapy for incompletely resected ependymoma, and observation for completely resected, supratentorial ependymoma. J Clin Oncol. 2019;37:974–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Perla A, Fratini L, Cardoso PS, Nör C, Brunetto AT, Brunetto AL, et al. Histone deacetylase inhibitors in pediatric brain cancers: biological activities and therapeutic potential. Front Cell Dev Biol. 2020;8:546.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Wang Z, Qin G, Zhao TC. HDAC4: mechanism of regulation and biological functions. Epigenomics. 2014;6:139–50.

    Article  CAS  PubMed  Google Scholar 

  26. Mack SC, Pajtler KW, Chavez L, Okonechnikov K, Bertrand KC, Wang XX, et al. Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling. Nature. 2018;553:101–5.

    Article  CAS  PubMed  Google Scholar 

  27. Thandapani P. Super-enhancers in cancer. Pharmacol Ther. 2019;199:129–38.

    Article  CAS  PubMed  Google Scholar 

  28. Amodio N, Stamato MA, Gullà AM, Morelli E, Romeo E, Raimondi L, et al. Therapeutic targeting of miR-29b/HDAC4 epigenetic loop in multiple myeloma. Mol Cancer Ther. 2016;15:1364–75.

    Article  CAS  PubMed  Google Scholar 

  29. Cai J-Y, Xu T-T, Wang Y, Chang J-J, Li J, Chen X-Y, et al. Histone deacetylase HDAC4 promotes the proliferation and invasion of glioma cells. Int J Oncol. 2018;53:2758–68.

    CAS  PubMed  Google Scholar 

  30. Zeng L-S, Yang X-Z, Wen Y-F, Mai S-J, Wang M-H, Zhang M-Y, et al. Overexpressed HDAC4 is associated with poor survival and promotes tumor progression in esophageal carcinoma. Aging. 2016;8:1236–48.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wilson AJ, Byun DS, Nasser S, Murray LB, Ayyanar K, Arango D, et al. HDAC4 promotes growth of colon cancer cells via repression of p21. Mol Biol Cell. 2008;19:4062–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cheng C, Yang J, Li S-W, Huang G, Li C, Min W-P, et al. HDAC4 promotes nasopharyngeal carcinoma progression and serves as a therapeutic target. Cell Death Dis. 2021;12:137–137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li J, Yan X, Liang C, Chen H, Liu M, Wu Z, et al. Comprehensive analysis of the differential expression and prognostic value of histone deacetylases in glioma. Front Cell Dev Biol. 2022;10:840759.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Becher OJ. HDAC inhibitors to the rescue in sonic hedgehog medulloblastoma. Neuro Oncol. 2019;21:1091–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lu Y, Stuart JH, Talbot-Cooper C, Agrawal-Singh S, Huntly B, Smid AI, et al. Histone deacetylase 4 promotes type I interferon signaling, restricts DNA viruses, and is degraded via vaccinia virus protein C6. Proc Natl Acad Sci USA. 2019;116:11997–2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yang Q, Tang J, Pei R, Gao X, Guo J, Xu C, et al. Host HDAC4 regulates the antiviral response by inhibiting the phosphorylation of IRF3. J Mol Cell Biol. 2019;11:158–69.

    Article  CAS  PubMed  Google Scholar 

  37. Martini M, Testi MG, Pasetto M, Picchio MC, Innamorati G, Mazzocco M, et al. IFN-gamma-mediated upmodulation of MHC class I expression activates tumor-specific immune response in a mouse model of prostate cancer. Vaccine. 2010;28:3548–57.

    Article  CAS  PubMed  Google Scholar 

  38. Zaidi MR, Merlino G. The two faces of interferon-γ in cancer. Clin Cancer Res. 2011;17:6118–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lee JH, Park SM, Kim OS, Lee CS, Woo JH, Park SJ, et al. Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gamma-stimulated brain astrocytes. Mol Cell. 2009;35:806–17.

    Article  CAS  PubMed  Google Scholar 

  40. Zapatka M, Borozan I, Brewer DS, Iskar M, Grundhoff A, Alawi M, et al. The landscape of viral associations in human cancers. Nat Genet. 2020;52:320–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pidugu VK, Pidugu HB, Wu M-M, Liu C-J, Lee T-C. Emerging functions of human IFIT proteins in cancer. Front Mol Biosci. 2019;6:148.

  42. Fensterl V, Sen GC. Interferon-induced ifit proteins: their role in viral pathogenesis. J Virol. 2015;89:2462–8.

    Article  PubMed  Google Scholar 

  43. Wu S-Y, Fu T, Jiang Y-Z, Shao Z-M. Natural killer cells in cancer biology and therapy. Mol Cancer. 2020;19:120–120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mishra R, Welsh R, Szomolanyi-Tsuda E. NK cells and virus-related cancers. Crit Rev Oncog. 2014;19:107–19.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Xu Y-H, Li Z-L, Qiu S-F. IFN-γ induces gastric cancer cell proliferation and metastasis through upregulation of integrin β3-mediated NF-κB signaling. Transl Oncol. 2018;11:182–92.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Ozawa T, Arora S, Szulzewsky F, Juric-Sekhar G, Miyajima Y, Bolouri H, et al. A de novo mouse model of C11orf95-RELA fusion-driven ependymoma identifies driver functions in addition to NF-κB. Cell Rep. 2018;23:3787–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Donson AM, Amani V, Warner EA, Griesinger AM, Witt DA, Levy JMM, et al. Identification of FDA-approved oncology drugs with selective potency in high-risk childhood ependymoma. Mol Cancer Ther. 2018;17:1984–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hanson JE, La H, Plise E, Chen Y-H, Ding X, Hanania T, et al. SAHA enhances synaptic function and plasticity in vitro but has limited brain availability in vivo and does not impact cognition. PLoS ONE. 2013;8:e69964–e69964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Alqudah M, Al‑Samman R, Azaizeh M, Alzoubi K. Amlodipine inhibits proliferation, invasion, and colony formation of breast cancer cells. Biomed Rep. 2022;16:50–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Löscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRX. 2005;2:86–98.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Sabnis DH, Storer LCD, Liu J-F, Jackson HK, Kilday JP, Grundy RG, et al. A role for ABCB1 in prognosis, invasion and drug resistance in ependymoma. Sci Rep. 2019;9:10290–10290.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Maklad A, Sharma A, Azimi I. Calcium signaling in brain cancers: roles and therapeutic targeting. Cancers. 2019;11:145–145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dr. Kristian Pajtler for providing information on the survival clinical data of EPN patients (GSE64415 dataset). We also thank Dr. Maristella B. F. Reis and Dr. Paulo H. S. Klinger for their assistance with the clinical data. Finally, we want to thank and acknowledge patients and families affected by ependymoma for their generous contributions to these studies.

Funding

This study was supported by the São Paulo Research Foundation (FAPESP)- grant no 2014/20341–0, 2018/23372–4/Brazil to G.R.S, 2021/11402–9/Brazil to G.R.S; Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES) – Finance Code 001; National Council for Scientific and Technological Development (CNPq), 140140–2019–0. We also had support of FAEPA (Fundação de Amparo ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto-USP).

Author information

Author notes

  1. These authors contributed equally: Luiz Gonzaga Tone, Elvis Terci Valera.

Authors and Affiliations

  1. Department of Genetics, Ribeirão Preto Medical School, 3900, Bandeirantes Avenue, Ribeirão Preto, SP, 14049-900, Brazil

    Graziella R. de Sousa, Luis F. P. Nagano, Pablo S. Chagas, Carlos A. Scrideli & Luiz G. Tone

  2. Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA

    Graziella R. de Sousa, Andrew M. Donson & Nicholas K. Foreman

  3. Department of Pediatrics, Ribeirão Preto Medical School, 3900, Bandeirantes Avenue, Ribeirão Preto, SP, 14049-900, Brazil

    Karina B. Salomão, Luciana C. Veronez, Rosane G. de Paula Queiroz, Carlos A. Scrideli, Luiz G. Tone & Elvis T. Valera

  4. RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA

    Kent A. Riemondy

  5. Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

    Pablo S. Chagas

  6. Department of Pathology, Ribeirão Preto Medical School, 3900, Bandeirantes Avenue, Ribeirão Preto, SP, 14049-900, Brazil

    Fabiano P. Saggioro

  7. Laboratory of Molecular and Cellular Biology (LIM 15), Department of Neurology, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, 01246-903, SP, Brazil

    Suely K. N. Marie

  8. Centro Infantil Boldrini, Campinas, SP, Brazil

    José A. Yunes, Izilda A. Cardinalli & Silvia R. Brandalise

  9. Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children’s Hospital Colorado, Aurora, CO, 80045, USA

    Andrew M. Donson & Nicholas K. Foreman

Authors
  1. Graziella R. de Sousa
    View author publications

    Search author on:PubMed Google Scholar

  2. Karina B. Salomão
    View author publications

    Search author on:PubMed Google Scholar

  3. Luis F. P. Nagano
    View author publications

    Search author on:PubMed Google Scholar

  4. Kent A. Riemondy
    View author publications

    Search author on:PubMed Google Scholar

  5. Pablo S. Chagas
    View author publications

    Search author on:PubMed Google Scholar

  6. Luciana C. Veronez
    View author publications

    Search author on:PubMed Google Scholar

  7. Fabiano P. Saggioro
    View author publications

    Search author on:PubMed Google Scholar

  8. Suely K. N. Marie
    View author publications

    Search author on:PubMed Google Scholar

  9. José A. Yunes
    View author publications

    Search author on:PubMed Google Scholar

  10. Izilda A. Cardinalli
    View author publications

    Search author on:PubMed Google Scholar

  11. Silvia R. Brandalise
    View author publications

    Search author on:PubMed Google Scholar

  12. Rosane G. de Paula Queiroz
    View author publications

    Search author on:PubMed Google Scholar

  13. Carlos A. Scrideli
    View author publications

    Search author on:PubMed Google Scholar

  14. Andrew M. Donson
    View author publications

    Search author on:PubMed Google Scholar

  15. Nicholas K. Foreman
    View author publications

    Search author on:PubMed Google Scholar

  16. Luiz G. Tone
    View author publications

    Search author on:PubMed Google Scholar

  17. Elvis T. Valera
    View author publications

    Search author on:PubMed Google Scholar

Contributions

GRS planned and conducted all experiments, in silico analysis, drafted and wrote, and critically reviewed the manuscript. KBS, PSC, and LCV helped with the bench methodology and investigation and critically read the manuscript. LFPN and KAR performed bioinformatics analysis and interpretation. FPS performed the histopathologic analysis. SKNM, SRB, JAY, IAC, and RGPQ provided reagents, data, consultation, and editing of the manuscript. CAS, AMD, NKF, ETV, and LGT provided the consultation review and editing of the manuscript. All authors critically wrote, edited, and reviewed the manuscript.

Corresponding author

Correspondence to Graziella R. de Sousa.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This research was submitted to and approved by the HC/FMRP-USP Research Ethics Committee (CAAE no 40768820.4.0000.5440).

Informed consent

All samples were obtained after receiving informed consent from all participant´s legal guardians included 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

de Sousa, G.R., Salomão, K.B., Nagano, L.F.P. et al. Identification of HDAC4 as a potential therapeutic target and prognostic biomarker for ZFTA-fused ependymomas. Cancer Gene Ther 30, 1105–1113 (2023). https://doi.org/10.1038/s41417-023-00616-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41417-023-00616-z

Search

Advanced search

Quick links