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• W2999161782 abstract "Abstract Purpose: 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. Experimental Design: Super-enhancer regions were characterized through chromatin immunoprecipitation sequencing (ChIP-seq). RT-qPCR was used to detect the mRNA level of CDK7 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 in vitro and in vivo assays were performed to assess the effects of CDK7 knockdown and THZ2 treatment in osteosarcoma. Results: 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 in vitro and in vivo. Conclusions: 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." @default.
• W2999161782 created "2020-01-23" @default.
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• W2999161782 date "2020-06-01" @default.
• W2999161782 modified "2023-10-14" @default.
• W2999161782 title "Targeting Super-Enhancer–Associated Oncogenes in Osteosarcoma with THZ2, a Covalent CDK7 Inhibitor" @default.
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• W2999161782 doi "https://doi.org/10.1158/1078-0432.ccr-19-1418" @default.
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