Abstract
Osteosarcoma, the most common pediatric bone tumor, is an aggressive heterogeneous malignancy defined by complex chromosomal aberrations. Overall survival rates remain at ~70%, but patients with chemoresistant or metastatic disease have extremely poor outcomes of <30%. A subgroup of tumors harbor amplification of chromosome 8q24.2 and increased expression of the oncogenic long noncoding RNA (lncRNA) Plasmacytoma Variant Translocation-1 (PVT-1), which is associated with an extremely poor clinical prognosis. This study demonstrates that PVT-1 is critical for osteosarcoma tumor-initiation potential. Chromatin Hybridization by RNA Purification analysis identified Tripartite-Motif Containing Family 28 (TRIM28) as a novel PVT-1 binding partner. Mechanistically, co-immunoprecipitation studies showed the PVT-1/TRIM28 complex binds and increases SUMOylation of phosphatidylinositol 3-kinase catalytic subunit type 3 (Vps34), which leads to enhanced ubiquitination and degradation of tumor suppressor complex 2 (TSC2), thus contributing to increased self-renewal and stem cell phenotypes. Furthermore, we identified that osteosarcoma cells with increased PVT-1 have enhanced sensitivity to the SUMOylation inhibitor, TAK-981. Altogether, this study elucidated a role for PVT-1 in the enhancement of cancer stem-like behaviors, including migration and invasion, in osteosarcoma, and identified the novel PVT-1/TRIM28 axis signaling cascade as a potential therapeutic target for osteosarcoma treatment.
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Acknowledgements
We would like to acknowledge the Advanced Technologies Core services at the Baylor College of Medicine. This work was funded by The Faris D. Virani Ewing Sarcoma Center (to JTY). SVT was partially supported by Cancer Prevention Institute of Texas (CPRIT) RP160283, KR and CC were partially supported by (CPRIT) RP170005, NIH P30 shared resource grant CA125123, and NIEHS P30 Center grant 1P30ES030285; CPRIT Core Facility Support Award (CPRIT-RP180672), the NIH (CA125123 and RR024574 to the Cytometry and Cell Sorting Core at Baylor College of Medicine); and Core Facility Award (CPRIT-RP170005 to Proteomics and Metabolomics Core at Baylor College of Medicine). We thank Dr. Suzanne Fuqua and Dr. Xiang Zhang for generously providing the breast cancer cell lines.
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SVT and JTY conceived the project. SVT, TDP, KR, CC, TKM, PHR, and JTY designed the experiments and analyzed the data. SVT, NR, ML, MN, KN, HRK, and SH performed the experiments, in part, and analyzed the data. JTY supervised the study. SVT and JTY wrote and revised the manuscript. All authors reviewed and approved the paper.
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Tsang, S.V., Rainusso, N., Liu, M. et al. LncRNA PVT-1 promotes osteosarcoma cancer stem-like properties through direct interaction with TRIM28 and TSC2 ubiquitination. Oncogene 41, 5373–5384 (2022). https://doi.org/10.1038/s41388-022-02538-w
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DOI: https://doi.org/10.1038/s41388-022-02538-w
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