YBX1-interacting small RNAs and RUNX2 can be blocked in primary bone cancer using CADD522

Green, Darrell ORCID: https://orcid.org/0000-0002-0217-3322, Singh, Archana, Tippett, Victoria L., Tattersall, Luke, Shah, Karan M., Siachisumo, Chileleko, Ward, Nicole J., Thomas, Paul, Carter, Simon, Jeys, Lee, Sumathi, Vaiyapuri, McNamara, Iain R., Elliott, David J., Gartland, Alison, Dalmay, Tamas ORCID: https://orcid.org/0000-0003-1492-5429 and Fraser, William D. (2023) YBX1-interacting small RNAs and RUNX2 can be blocked in primary bone cancer using CADD522. Journal of Bone Oncology, 39. ISSN 2212-1374

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Abstract

Primary bone cancer (PBC) comprises several subtypes each underpinned by distinctive genetic drivers. This driver diversity produces novel morphological features and clinical behaviour that serendipitously makes PBC an excellent metastasis model. Here, we report that some transfer RNA-derived small RNAs termed tRNA fragments (tRFs) perform as a constitutive tumour suppressor mechanism by blunting a potential pro-metastatic protein-RNA interaction. This mechanism is reduced in PBC progression with a gradual loss of tRNAGlyTCC cleavage into 5’ end tRF-GlyTCC when comparing low-grade, intermediate-grade and high-grade patient tumours. We detected recurrent activation of miR-140 leading to upregulated RUNX2 expression in high-grade patient tumours. Both tRF-GlyTCC and RUNX2 share a sequence motif in their 3’ ends that matches the YBX1 recognition site known to stabilise pro-metastatic mRNAs. Investigating some aspects of this interaction network, gain- and loss-of-function experiments using small RNA mimics and antisense LNAs, respectively, showed that ectopic tRF-GlyTCC reduced RUNX2 expression and dispersed 3D micromass architecture in vitro. iCLIP sequencing revealed YBX1 physical binding to the 3’ UTR of RUNX2. The interaction between YBX1, tRF-GlyTCC and RUNX2 led to the development of the RUNX2 inhibitor CADD522 as a PBC treatment. CADD522 assessment in vitro revealed significant effects on PBC cell behaviour. In xenograft mouse models, CADD522 as a single agent without surgery significantly reduced tumour volume, increased overall and metastasis-free survival and reduced cancer-induced bone disease. Our results provide insight into PBC molecular abnormalities that have led to the identification of new targets and a new therapeutic.

Item Type:	Article
Additional Information:	DATA AVAILABILITY: The raw sRNA and iCLIP sequencing data have been deposited at Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo) under the accessions GSE86576 and GSE212178, respectively. Other data that support the study findings are available from the corresponding author upon request. ACKNOWLEDGEMENTS: The Sir William Coxen Trust Fund and Big C funded this work. C.S. and D.J.E. are funded by the BBSRC (grant BB/S008039/1). D.G. is supported by The Difference Campaign; we thank David Ellis, his team and the generous donors.
Uncontrolled Keywords:	sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School Faculty of Science > School of Biological Sciences
UEA Research Groups:	Faculty of Science > Research Groups > Plant Sciences Faculty of Medicine and Health Sciences > Research Groups > Musculoskeletal Medicine Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	LivePure Connector
Date Deposited:	01 Mar 2023 13:31
Last Modified:	19 Oct 2023 03:33
URI:	https://ueaeprints.uea.ac.uk/id/eprint/91314
DOI:	10.1016/j.jbo.2023.100474

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