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The DNA/RNA helicase DHX9 orchestrates the KDM2B-mediated transcriptional regulation of YAP1 in Ewing sarcoma

Oncogene volume 43, pages 225–234 (2024)Cite this article

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Abstract

Ewing sarcomas (ES) are aggressive paediatric tumours of bone and soft tissues. Resistance to chemotherapy and high propensity to metastasize remain the main causes of treatment failure. Thus, identifying novel targets for alternative therapeutic approaches is urgently needed. DNA/RNA helicases are emerging as crucial regulators of many cellular processes often deregulated in cancer. Among them, DHX9 is up-regulated in ES and collaborates with EWS-FLI1 in ES transformation. We report that DHX9 silencing profoundly impacts on the oncogenic properties of ES cells. Transcriptome profiling combined to bioinformatic analyses disclosed a gene signature commonly regulated by DHX9 and the Lysine Demethylase KDM2B, with the Hippo pathway regulator YAP1 as a prominent target. Mechanistically, we found that DHX9 enhances H3K9 chromatin demethylation by KDM2B and favours RNA Polymerase II recruitment, thus promoting YAP1 expression. Conversely, EWS-FLI1 binding to the promoter represses YAP1 expression. These findings identify the DHX9/KDM2B complex as a new druggable target to counteract ES malignancy.

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Fig. 1: Enhanced DHX9 expression is associated with the tumorigenic phenotype.
Fig. 2: Downregulation of DHX9 expression decreases tumour growth in vivo.
Fig. 3: DHX9 controls the expression of tumorigenic-related genes in ES cells.
Fig. 4: DHX9 regulated genes significantly overlap with KDM2B signature in ES.
Fig. 5: YAP1 expression is modulated by DHX9 and KDM2B in ES cells.
Fig. 6: DHX9 and KDM2B form a molecular complex to regulate YAP1 expression.
Fig. 7: EWS-FLI1 acts as a transcriptional repressor of YAP1 expression.
Fig. 8: DHX9 knockdown impacts YAP1 expression in vivo.

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Data availability

The data generated in this study are publicly available in Gene Expression Omnibus (GEO) at GSE214257.

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Acknowledgements

This work was supported by grants from the Associazione Italiana Ricerca sul Cancro (AIRC) (IG21877) to MPP, and from the Italian Ministry of Health (SG-2019-12371596) to LC.

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Authors and Affiliations

  1. Laboratory of Cellular and Molecular Neurobiology, IRCCS Santa Lucia Foundation, Rome, Italy

    Lidia Chellini & Maria Paola Paronetto

  2. Plaisant Polo Tecnologico s.r.l, Castel Romano, Rome, Italy

    Marzia Scarfò

  3. Section of Human Anatomy, Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy

    Davide Bonvissuto & Claudio Sette

  4. GSTeP-Organoids Core Facility, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy

    Claudio Sette

  5. Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, Rome, Italy

    Maria Paola Paronetto

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Contributions

Conceptualization, LC and MPP; methodology, LC; formal analysis, LC; investigation, LC and MPP; IHC, DB; mouse xenografts, LC and MS; data curation, LC and MPP; writing-original draft preparation, LC and MPP; writing-review and editing, CS and MPP; supervision, MPP; project administration, MPP; funding acquisition, LC and MPP. The authors have read and agreed to the published version of the manuscript.

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Correspondence to Lidia Chellini or Maria Paola Paronetto.

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Chellini, L., Scarfò, M., Bonvissuto, D. et al. The DNA/RNA helicase DHX9 orchestrates the KDM2B-mediated transcriptional regulation of YAP1 in Ewing sarcoma. Oncogene 43, 225–234 (2024). https://doi.org/10.1038/s41388-023-02894-1

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