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

by Selleckchem | Dec 20 2023

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.

Comments:

It seems like you've provided a detailed and specific summary of a research study or paper related to primary bone cancer (PBC). The information you've presented involves the role of transfer RNA-derived small RNAs (tRFs) as a tumor suppressor mechanism and their connection to pro-metastatic protein-RNA interactions in PBC. The study also discusses the reduction of this mechanism in PBC progression, the involvement of miR-140 and upregulated RUNX2 expression in high-grade tumors, and the shared sequence motif between tRF-GlyTCC and RUNX2 that matches the YBX1 recognition site.

Furthermore, the research explores gain- and loss-of-function experiments using small RNA mimics and antisense LNAs, demonstrating that ectopic tRF-GlyTCC reduces RUNX2 expression and affects the 3D micromass architecture in vitro. iCLIP sequencing reveals YBX1's physical binding to the 3' UTR of RUNX2, and this interaction between YBX1, tRF-GlyTCC, and RUNX2 leads to the development of the RUNX2 inhibitor CADD522 as a potential treatment for PBC.

The study includes assessments of CADD522 in vitro, showing significant effects on PBC cell behavior. In xenograft mouse models, CADD522 as a single agent, without surgery, is reported to significantly reduce tumor volume, increase overall and metastasis-free survival, and decrease cancer-induced bone disease.

Overall, this research provides valuable insights into the molecular abnormalities associated with PBC and identifies potential therapeutic targets, with CADD522 emerging as a promising treatment option for PBC.