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

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.

Bone cancer: Disease-promoting DNA regions revealed as therapeutic targets

Insight into a molecular pathway involved in an aggressive bone cancer has suggested a new approach to its treatment. Osteosarcoma usually develops in growing bone tissue, but often spreads to other organs, consequently reducing survival. The molecular mechanisms behind osteosarcoma are not fully understood. A team led by Shuibin Lin from Sun Yat-sen University investigated the role of MYC, a gene that is important in other cancers. They found that increased expression of MYC is associated with the spread of osteosarcoma and a poor prognosis because the protein product of MYC activates many super-enhancers, regions of DNA that increase the expression of cancer-related genes. Inhibition of the super-enhancers suppressed growth and spreading of osteosarcoma in cultured cells and a mouse model, suggesting a novel therapeutic approach to osteosarcoma.

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