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

Lookup NU author(s): Chile Siachisumo, Professor David Elliott

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2023 The Author(s)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.


Publication metadata

Author(s): Green D, Singh A, Tippett VL, Tattersall L, Shah KM, Siachisumo C, Ward NJ, Thomas P, Carter S, Jeys L, Sumathi V, McNamara I, Elliott DJ, Gartland A, Dalmay T, Fraser WD

Publication type: Article

Publication status: Published

Journal: Journal of Bone Oncology

Year: 2023

Volume: 39

Print publication date: 01/04/2023

Online publication date: 05/03/2023

Acceptance date: 28/02/2023

Date deposited: 28/03/2023

ISSN (print): 2212-1366

ISSN (electronic): 2212-1374

Publisher: Elsevier GmbH

URL: https://doi.org/10.1016/j.jbo.2023.100474

DOI: 10.1016/j.jbo.2023.100474


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Funding

Funder referenceFunder name
14-08R
BB/S008039/1Biotechnology and Biological Sciences Research Council (BBSRC)
The Difference Campaign

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