journal contribution
posted on 2023-03-31, 21:43 authored by Jiajun Zhang, Weihai Liu, Changye Zou, Zhiqiang Zhao, Yuanying Lai, Zhi Shi, Xianbiao Xie, Gang Huang, Yongqian Wang, Xuelin Zhang, Zepei Fan, Qiao Su, Junqiang Yin, Jingnan Shen <p>Enrichment analysis of THZ2-sensitive genes in osteosarcoma.</p>
Funding
National Natural Science Foundation of China
Natural Science Foundation of Guangdong Province
Science &Technology Planning Project of Guangzhou City
Sun Yat-sen University
Fundamental Research Funds for the Central Universities
Scientific Research 3 × 3 Project of Sun Yat-sen University
History
ARTICLE ABSTRACT
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 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.
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.
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.
