Abstract 4883: CDK8: A new druggable mediator of NFκB activity

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-10, Vol.74 (19_Supplement), p.4883-4883
• Main Authors: Chen, Mengqian, McDermott, Martina, Yang, Zhengguan, Liang, Jiaxin, Schools, Gary P., Lim, Chang-uk, Lu, Tao, George, Stark R., West, Deborah K., Porter, Donald C., Broude, Eugenia V., Roninson, Igor B.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2014-4883

Cyclin-dependent kinase 8 (CDK8) is a transcription-regulating oncogenic serine kinase, which mediates several cancer-related transcriptional pathways such as beta-catenin, TP53, TGF-beta and HIF1A. We have recently discovered the first selective small-molecule inhibitors of CDK8 and its closely related isoform CDK19 and showed that these inhibitors block chemotherapy-induced tumor-promoting paracrine activities of both tumor and normal cells (Porter et al., PNAS 109, 13799, 2012). Since transcription factor NFκB plays a key role in damage-induced expression of tumor-promoting cytokines, we have tested the effects of a highly selective CDK8/19 inhibitor Senexin A on NFκB-induced transcription. Senexin A treatment or knockdown of CDK8 by shRNA inhibits transcriptional activation of NFκB-responsive promoters and of acutely responsive cytokine genes (such as CXCL1, CXCL2, IL8 and CCL20), by TNFα, a canonical NFκB activator, in several cell lines. CDK8 inhibition did not prevent nuclear translocation of active NFκB proteins. Chromatin immunoprecipitation (ChIP) analysis of HEK293 cells, untreated or treated with TNFα or Senexin A, singly or in combination, showed that CDK8 is recruited to NFκB early-responsive genes upon TNFα treatment, but the CDK8 inhibitor did not prevent the recruitment of NFκB, CDK8 or RNA Polymerase II (Pol II) to the target genes. However, CDK8 kinase activity was found to be required for C-terminal domain phosphorylation (both at S2 and S5 residues) of Pol II associated with the target genes, which is needed for the elongation of their NFκB-initiated transcription. In contrast, Pol II phosphorylation at constitutively expressed genes is not dependent on CDK8 kinase activity. These results suggest that CDK8 inhibitors may exert their effects against the activation of tumor-promoting and pro-inflammatory secreted factors in the tumor microenvironment by preventing transcriptional activation of NFκB-induced genes. Citation Format: Mengqian Chen, Martina McDermott, Zhengguan Yang, Jiaxin Liang, Gary P. Schools, Chang-uk Lim, Tao Lu, Stark R. George, Deborah K. West, Donald C. Porter, Eugenia V. Broude, Igor B. Roninson. CDK8: A new druggable mediator of NFκB activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4883. doi:10.1158/1538-7445.AM2014-4883