Targeting Super-Enhancer-Associated Oncogenes in Osteosarcoma with THZ2, a Covalent CDK7 Inhibitor

• Published in: Clinical cancer research 2020-06, Vol.26 (11), p.2681-2692
• Main Authors: Zhang, Jiajun, Liu, Weihai, Zou, Changye, Zhao, Zhiqiang, Lai, Yuanying, Shi, Zhi, Xie, Xianbiao, Huang, Gang, Wang, Yongqian, Zhang, Xuelin, Fan, Zepei, Su, Qiao, Yin, Junqiang, Shen, Jingnan
• Format: Article
• Language: English
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-1418

Malignancy of cancer cells depends on the active transcription of tumor-associated genes. Recently, unique clusters of transcriptional enhancers, termed super-enhancers, have been reported to drive the expression of genes that define cell identity. In this study, we characterized specific super-enhancer-associated genes of osteosarcoma, and explored their potential therapeutic value. Super-enhancer regions were characterized through chromatin immunoprecipitation sequencing (ChIP-seq). RT-qPCR was used to detect the mRNA level of in patient specimens and confirm the regulation of sensitive oncogenes by THZ2. The phosphorylation of the initiation-associated sites of RNA polymerase II (RNAPII) C-terminal repeat domain (CTD) was measured using Western blotting. Microarray expression analysis was conducted to explore transcriptional changes after THZ2 treatment. A variety of and assays were performed to assess the effects of CDK7 knockdown and THZ2 treatment in osteosarcoma. Super-enhancers were associated with oncogenic transcripts and key genes encoding cell-type-specific transcription factors in osteosarcoma. Knockdown of transcription factor CDK7 reduced phosphorylation of the RNAPII CTD, and suppressed the growth and metastasis of osteosarcoma. A new specific CDK7 inhibitor, THZ2, suppressed cancer biology by inhibition of transcriptional activity. Compared with typical enhancers, osteosarcoma super-enhancer-associated oncogenes were particular vulnerable to this transcriptional disruption. THZ2 exhibited a powerful anti-osteosarcoma effect and . Super-enhancer-associated genes contribute to the malignant potential of osteosarcoma, and selectively targeting super-enhancer-associated oncogenes with the specific CDK7 inhibitor THZ2 might be a promising therapeutic strategy for patients with osteosarcoma.