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Open AccessArticle

SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line

1
Department of Orthopaedic Surgery, Experimental Orthopaedics, Centre for Medical Biotechnology (ZMB/Biopark 1), University of Regensburg, 93053 Regensburg, Germany
2
Institute of Microbiology and Hygiene, University Hospital Regensburg, 93053 Regensburg, Germany
3
Department of Dermatology, University Medical Center Regensburg, 93053 Regensburg, Germany
4
Department of Pediatric Surgery, Dr. von Haunersche’s Children’s Hospital, LMU, 80337 Munich, Germany
5
Department of Orthopaedic Surgery, Campus Großhadern, LMU, 81377 Munich, Germany
6
Department of Orthopaedic Surgery, Klinikum Rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany
7
Department of Trauma Surgery and Orthopaedics, Krankenhaus Agatharied, 83734 Hausham, Germany
8
Center for Translational Cancer Research (TranslaTUM), Radiation Immuno Oncology Group, Klinikum Rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany
9
Department of Pathology, Technical University of Munich (TMU), 80333 Munich, Germany
10
Department of Sarcomas and Musculoskeletal Tumors, Barmherzige Brüder Hospital, 93049 Regensburg, Germany
11
Department of Oral and Maxillofacial Surgery, Center for Medical Biotechnology, University Hospital Regensburg, 93053 Regensburg, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(20), 7627; https://doi.org/10.3390/ijms21207627
Received: 21 September 2020 / Revised: 10 October 2020 / Accepted: 12 October 2020 / Published: 15 October 2020
(This article belongs to the Special Issue Transcription Factors in Cancer)
As most chemotherapeutic drugs are ineffective in the treatment of chondrosarcoma, we studied the expression pattern and function of SOX9, the master transcription factor for chondrogenesis, in chondrosarcoma, to understand the basic molecular principles needed for engineering new targeted therapies. Our study shows an increase in SOX9 expression in chondrosarcoma compared to normal cartilage, but a decrease when the tumors are finally defined as dedifferentiated chondrosarcoma (DDCS). In DDCS, SOX9 is almost completely absent in the non-chondroid, dedifferentiated compartments. CRISPR/Cas9-mediated knockout of SOX9 in a human chondrosarcoma cell line (HTB94) results in reduced proliferation, clonogenicity and migration, accompanied by an inability to activate MMP13. In contrast, adhesion, apoptosis and polyploidy formation are favored after SOX9 deletion, probably involving BCL2 and survivin. The siRNA-mediated SOX9 knockdown partially confirmed these results, suggesting the need for a certain SOX9 threshold for particular cancer-related events. To increase the efficacy of chondrosarcoma therapies, potential therapeutic approaches were analyzed in SOX9 knockout cells. Here, we found an increased impact of doxorubicin, but a reduced sensitivity for oncolytic virus treatment. Our observations present novel insight into the role of SOX9 in chondrosarcoma biology and could thereby help to overcome the obstacle of drug resistance and limited therapy options. View Full-Text
Keywords: SOX9; transcription factor; chondrosarcoma; polyploidy; MMP13; CRISPR/Cas9 SOX9; transcription factor; chondrosarcoma; polyploidy; MMP13; CRISPR/Cas9
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MDPI and ACS Style

Stöckl, S.; Lindner, G.; Li, S.; Schuster, P.; Haferkamp, S.; Wagner, F.; Prodinger, P.M.; Multhoff, G.; Boxberg, M.; Hillmann, A.; Bauer, R.J.; Grässel, S. SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line. Int. J. Mol. Sci. 2020, 21, 7627. https://doi.org/10.3390/ijms21207627

AMA Style

Stöckl S, Lindner G, Li S, Schuster P, Haferkamp S, Wagner F, Prodinger PM, Multhoff G, Boxberg M, Hillmann A, Bauer RJ, Grässel S. SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line. International Journal of Molecular Sciences. 2020; 21(20):7627. https://doi.org/10.3390/ijms21207627

Chicago/Turabian Style

Stöckl, Sabine; Lindner, Georg; Li, Shushan; Schuster, Philipp; Haferkamp, Sebastian; Wagner, Ferdinand; Prodinger, Peter M.; Multhoff, Gabriele; Boxberg, Melanie; Hillmann, Axel; Bauer, Richard J.; Grässel, Susanne. 2020. "SOX9 Knockout Induces Polyploidy and Changes Sensitivity to Tumor Treatment Strategies in a Chondrosarcoma Cell Line" Int. J. Mol. Sci. 21, no. 20: 7627. https://doi.org/10.3390/ijms21207627

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