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CDK7 inhibition is a novel therapeutic strategy against GBM both in vitro and in vivo

Authors Meng W, Wang J, Wang B, Liu F, Li M, Zhao Y, Zhang C, Li Q, Chen J, Zhang L, Tang Y, Ma J

Received 13 August 2018

Accepted for publication 11 October 2018

Published 15 November 2018 Volume 2018:10 Pages 5747—5758

DOI https://doi.org/10.2147/CMAR.S183696

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Andrew Yee

Peer reviewer comments 3

Editor who approved publication: Dr Ahmet Emre Eskazan


Wei Meng,1,* Jiajia Wang,1,* Baocheng Wang,1,* Fang Liu,2 Meng Li,2 Yang Zhao,1 Chenran Zhang,1 Qifeng Li,1 Juxiang Chen,3 Liye Zhang,4 Yujie Tang,1,2 Jie Ma1

1Department of Pediatric Neurosurgery, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, People’s Republic of China; 4Zhang’s Laboratory, School of Life Science and Technology, Shanghai Tech University, Shanghai, People’s Republic of China

*These authors contributed equally to this work

Background:
Glioblastoma multiforme (GBM) remains to be one of the top lethal cancer types for adult to date. Current GBM therapies suffer greatly from the highly heterogeneous and adaptable nature of GBM cells, indicating an urgent need of alternative therapeutic options. In this study, we focused on identifying novel epigenetic targeted strategy against GBM.
Methods: A collection of epigenetic modulating small molecules were subjected to anti-GBM screening and the inhibitory effect of identified agent was validated both in vitro and in vivo. Genetic targeting approaches were also used to verify the on-target inhibitory effect of identified agent. Furthermore, the inhibitory mechanism of identified agent was investigated by integrative analyses of drug-treated GBM cells and GBM tumor databases.
Results: The covalent CDK7 inhibitor THZ1 was one of the top hits in our screening and its anti-GBM activity was confirmed both in vitro and in vivo. CDK7 inhibition through CRISPR-Cas9 or RNA interference also markedly disrupted GBM cell growth. Furthermore, analyses of multiple GBM tumor databases consistently revealed that CDK7 expression was significantly elevated in GBM compared with normal brain tissues and lower grade gliomas. Higher CDK7 expression was correlated with worse prognosis for both glioma and GBM. Mechanistically, THZ1 treatment led to considerable disruption of global gene transcription in GBM cells, preferentially targeting those associated with super-enhancers (SEs). We also showed that THZ1 sensitive and SE-related genes had important roles for GBM growth.
Conclusion:
Our study shows that targeting SE-associated transcription addiction by CDK7 inhibition could be an effective therapeutic strategy against GBM.

Keywords: THZ1, CDK7, GBM, epigenetic targeted therapy, transcriptional addiction

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