Aberrant EZHIP expression drives tumorigenesis in osteosarcoma

Wajih Jawhar, Geoffroy Danieau, Alva Annett, Takeaki Ishii, Andrea Bajic, Ana Castillo-Orozco, Brian Krug, Yara Faucher-Jabado, Justin Seyedmoomenkashi, Mostafa Saquib, Masoumeh Aghababazadeh, Marjan Khatami, Nadim Tawil, Damien Faury, Sungmi Jung, Ahmed Aoude, Robert E. Turcotte, Benjamin Ellezam, Thomas Sontag, Sylvie Langlois, Daniel Sinnett, Swneke D. Bailey, Lingxin Zhang, Dorothée Dal Soglio, Claudia L. Kleinman (), Nada Jabado () and Livia Garzia ()
Additional contact information
Wajih Jawhar: McGill University
Geoffroy Danieau: The Research Institute of the McGill University Health Center
Alva Annett: McGill University
Takeaki Ishii: The Research Institute of the McGill University Health Center
Andrea Bajic: McGill University
Ana Castillo-Orozco: The Research Institute of the McGill University Health Center
Brian Krug: McGill University
Yara Faucher-Jabado: The Research Institute of the McGill University Health Center
Justin Seyedmoomenkashi: The Research Institute of the McGill University Health Center
Mostafa Saquib: The Research Institute of the McGill University Health Center
Masoumeh Aghababazadeh: The Research Institute of the McGill University Health Center
Marjan Khatami: The Research Institute of the McGill University Health Center
Nadim Tawil: McGill University
Damien Faury: McGill University and the Research Institute of the McGill University Heath Centre
Sungmi Jung: McGill University Health Centre
Ahmed Aoude: McGill University Health Centre
Robert E. Turcotte: McGill University Health Centre
Benjamin Ellezam: Université de Montréal
Thomas Sontag: CHU Sainte-Justine
Sylvie Langlois: Université de Montréal and CHU Sainte-Justine Research Centre
Daniel Sinnett: CHU Sainte-Justine
Swneke D. Bailey: The Research Institute of the McGill University Health Center
Lingxin Zhang: Mount Sinai Hospital
Dorothée Dal Soglio: Université de Montréal
Claudia L. Kleinman: McGill University
Nada Jabado: McGill University
Livia Garzia: McGill University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Osteosarcomas (OS) are aggressive bone tumors known for their extensive structural variations and rare recurrent oncogenic driver mutations. In this study, we identify ectopic expression of the oncohistone-mimic EZHIP in 20% of patients across two independent OS cohorts. We demonstrate that reduced deposition of the repressive H3K27me3 mark correlates with poor histological response to neoadjuvant therapy, serving as a predictor of patient outcomes. Through gain- and loss-of-function experiments, we provide functional evidence of the oncogenic activity of EZHIP in enhancing the aggressive characteristics of OS both in vitro and in vivo. EZHIP-induced epigenetic reprogramming reactivates developmental pathways and impedes the differentiation of mesenchymal progenitors, pushing them towards smooth muscle lineage commitment at the cost of other fates. Targeting residual H3K27me3 with EZH2 inhibitors may offer therapeutic benefit in EZHIP-expressing OS. Our findings highlight EZHIP expression as a prevalent driver in OS, offering insights into its pathogenic mechanisms and potential therapeutic strategies for this debilitating cancer.

Date: 2025
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DOI: 10.1038/s41467-025-61558-8

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