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Bone Res. 2018 Apr 4;6:11. doi: 10.1038/s41413-018-0009-8. eCollection 2018.

Super enhancer inhibitors suppress MYC driven transcriptional amplification and tumor progression in osteosarcoma.

Author information

1
1The Department of Dermatology, Yale University, New Haven, CT 06510 USA.
2
2Department of Musculoskeletal Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong China.
3
3State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060 Guangdong China.
4
4Institute for Advanced Study, Shenzhen University, Shenzhen, 518060 Guangdong China.
5
5Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC 20007 USA.
6
6Department of Oncology, Georgetown University Medical Center, Washington, DC 20007 USA.
7
7Department of Pharmaceutical and Health Economics, School of Pharmacy, University of Southern California, Los Angeles, CA 90089 USA.
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8Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong China.
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9Department of Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong China.
10
10Biobank of Eye, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060 Guangdong China.
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Contributed equally

Abstract

Osteosarcoma is the most common primary bone sarcoma that mostly occurs in young adults. The causes of osteosarcoma are heterogeneous and still not fully understood. Identification of novel, important oncogenic factors in osteosarcoma and development of better, effective therapeutic approaches are in urgent need for better treatment of osteosarcoma patients. In this study, we uncovered that the oncogene MYC is significantly upregulated in metastastic osteosarcoma samples. In addition, high MYC expression is associated with poor survival of osteosarcoma patients. Analysis of MYC targets in osteosarcoma revealed that most of the osteosarcoma super enhancer genes are bound by MYC. Treatment of osteosarcoma cells with super enhancer inhibitors THZ1 and JQ1 effectively suppresses the proliferation, migration, and invasion of osteosarcoma cells. Mechanistically, THZ1 treatment suppresses a large group of super enhancer containing MYC target genes including CDK6 and TGFB2. These findings revealed that the MYC-driven super enhancer signaling is crucial for the osteosarcoma tumorigenesis and targeting the MYC/super enhancer axis represents as a promising therapeutic strategy for treatment of osteosarcoma patients.

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