Journal article
Targeting the oncogenic TBX3:nucleolin complex to treat multiple sarcoma subtypes
- Abstract:
- Sarcomas are diverse cancers of mesenchymal origin, with compromised clinical management caused by insufficient diagnostic biomarkers and limited treatment options. The transcription factor TBX3 is upregulated in a diverse range of sarcoma subtypes, where it plays a direct oncogenic role, and it may thus represent a novel therapeutic target. To identify versatile ways to target TBX3, we performed affinity purification coupled by mass spectrometry to identify putative TBX3 protein cofactors that regulate its oncogenic activity in sarcomas. Here we identify and validate the multifunctional phosphoprotein nucleolin as a TBX3 cofactor. We show that nucleolin is co-expressed with TBX3 in several sarcoma subtypes and their expression levels positively correlate in sarcoma patients which are associated with poor prognosis. Furthermore, we demonstrate that nucleolin and TBX3 interact in chondrosarcoma, liposarcoma and rhabdomyosarcoma cells where they act together to enhance proliferation and migration and regulate a common set of tumor suppressor genes. Importantly, the nucleolin targeting aptamer, AS1411, exhibits selective anti-cancer activity in these cells and mislocalizes TBX3 and nucleolin to the cytoplasm which correlates with the re-expression of the TBX3/nucleolin target tumor suppressors <i>CDKN1A</i> (p21<sup>CIP1</sup>) and <i>CDKN2A</i> (p14<sup>ARF</sup>). Our findings provide the first evidence that TBX3 requires nucleolin to promote features of sarcomagenesis and that disruption of the oncogenic TBX3-nucleolin interaction by AS1411 may be a novel approach for treating sarcomas.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 3.8MB, Terms of use)
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- Publication website:
- https://e-century.us/files/ajcr/11/11/ajcr0137198.pdf
Authors
- Publisher:
- e-Century Publishing
- Journal:
- American Journal of Cancer Research More from this journal
- Volume:
- 11
- Issue:
- 11
- Pages:
- 5680-5700
- Place of publication:
- United States
- Publication date:
- 2021-11-15
- Acceptance date:
- 2021-10-08
- EISSN:
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2156-6976
- Pmid:
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34873487
- Language:
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English
- Keywords:
- Pubs id:
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1454761
- Local pid:
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pubs:1454761
- Deposit date:
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2023-06-21
Terms of use
- Copyright holder:
- Willmer et al
- Copyright date:
- 2021
- Rights statement:
- ©2021 The Authors. Published by e-Century Publishing Corporation, under the “Creative Commons Attribution Non- Commercial License”, enabling the unrestricted non-commercial use, distribution, and reproduction of the published article in any medium, provided that the original work is properly cited.
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