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

被引：104

作者：

Chen, Demeng ^{[1
]}

Zhao, Zhiqiang ^{[2
]}

Huang, Zixin ^{[3
]}

Chen, Du-Chu ^{[4
]}

Zhu, Xin-Xing ^{[4
]}

Wang, Yi-Ze ^{[4
]}

Yan, Ya-Wei ^{[4
]}

Tang, Shaojun ^{[5
,6
]}

Madhavan, Subha ^{[5
,6
]}

Ni, Weiyi ^{[7
]}

Huang, Zhan-Peng ^{[8
]}

Li, Wen ^{[9
]}

Ji, Weidong ^{[8
]}

Shen, Huangxuan ^{[3
,10
]}

Lin, Shuibin ^{[8
]}

Jiang, Yi-Zhou ^{[4
]}

机构：

[1] Yale Univ, Dept Dermatol, New Haven, CT 06510 USA

[2] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Musculoskeletal Oncol, Guangzhou 510080, Guangdong, Peoples R China

[3] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510060, Guangdong, Peoples R China

[4] Shenzhen Univ, Inst Adv Study, Shenzhen 518060, Guangdong, Peoples R China

[5] Georgetown Univ, Med Ctr, Innovat Ctr Biomed Informat, Washington, DC 20007 USA

[6] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA

[7] Univ Southern Calif, Sch Pharm, Dept Pharmaceut & Hlth Econ, Los Angeles, CA 90089 USA

[8] Sun Yat Sen Univ, Affiliated Hosp 1, Ctr Translat Med, Guangzhou 510080, Guangdong, Peoples R China

[9] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Surg, Guangzhou 510080, Guangdong, Peoples R China

[10] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Biobank Eye, Guangzhou 510060, Guangdong, Peoples R China

来源：

BONE RESEARCH | 2018年 / 6卷

基金：

中国国家自然科学基金;

关键词：

COVALENT CDK7 INHIBITOR; SQUAMOUS-CELL CARCINOMA; C-MYC; RNA-SEQ; CANCER; EXPRESSION; ONCOGENES; GENE; KINASE; TOPHAT;

D O I：

10.1038/s41413-018-0009-8

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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.

引用

页数：7

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