Targeted inhibition of cyclin-dependent kinase 7 (CDK7) via its covalent inhibitor THZ1 can suppress the growth of various cancers, while its roles on colorectal cancer (CRC) remain obscure. Here we report that the expression of CDK7 is upregulated in CRC cells and tissues. THZ1 exhibits high potency and selectivity against CRC cells both in vitro and in vivo via induction of cell apoptosis rather than cell cycle disruption. Intriguingly, THZ1 treatment increases the ability of epithelial mesenchymal transition (EMT) and in vivo metastasis to liver of CRC cells. Mechanistical studies reveal that THZ1 increases the expression of Snail, while not other EMT-transcription factors, via enhancing its protein stability rather than mRNA expression or translation. By screening Snail stability related factors via qRT-PCR, results indicate THZ1 and si-CDK7 decrease the expression of protein kinase D1 (PKD1) in CRC cells. Down regulation of PKD1 mediates THZ1 up regulated Snail via dephosphorylation of Snail Ser 11 and prevention of proteasome mediated degradation. Clinical analysis confirms that CDK7 is significantly (p < 0.05) negatively correlated with the expression of mesenchymal markers including FN1, VIM, and MMP2. CRC patients whose tumors expressing less CDK7/SNAI1 or PKD1/SNAI1 showed significant (p < 0.05) poorer overall survival (OS) rate as compared with those with greater levels. Collectively, our data suggest that targeted inhibition of CDK7 can trigger the metastasis of CRC during cancer development via PKD1/Snail axis, which imposes great challenge that inhibition of CDK7 is a potential approach for cancer treatment.
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This research was supported by the National Natural Science Foundation of China (Grant No. 81673454, No. 81672608, No. 81472470, No. 31801197, and No. 81572270), the Guangdong Natural Science Funds for Distinguished Young Scholar (No. 2014A030306025), the Hunan Young Talent, China (No.2017RS3051), the Pearl River S&T Nova Program of Guangzhou (No. 1517000390), and the Fundamental Research Funds for the Central Universities (Sun Yat-sen University) (16ykpy09).
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The authors declare that they have no conflict of interest.
Edited by G. Del Sal
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Cell Death & Differentiation (2019)