Mutated K-ras activates CDK8 to stimulate the epithelial-to-mesenchymal transition in pancreatic cancer in part via the Wnt/β-catenin signaling pathway

Xu, Wei; Wang, Ziwei; Zhang, Wei; Qian, Kun; Li, Hui; Kong, Dequan; Li, Yuqiang; Tang, Yucheng

doi:10.1016/j.canlet.2014.10.008

Cited by 113 publications

(99 citation statements)

References 52 publications

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“…CDK8/19 regulation is especially pertinent in cancers, where CDK8 positively regulates several cancer-relevant signaling pathways (5), including Wnt/β-catenin (9), the serum response network (6), TGFβ (10), HIF1α (7), and estrogen receptor (8). CDK8 has been identified as an oncogene implicated in colorectal (9), pancreatic (11), and breast (3,8,12,13) cancers and melanomas (14) and associated with the stem cell phenotype (15). CDK8/19 inhibition also has an antiproliferative effect in a subset of leukemias (16,17).…”

Section: Significancementioning

confidence: 99%

CDK8/19 Mediator kinases potentiate induction of transcription by NFκB

Chen

Liang

Jiang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

108

130

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The nuclear factor-κB (NFκB) family of transcription factors has been implicated in inflammatory disorders, viral infections, and cancer. Most of the drugs that inhibit NFκB show significant side effects, possibly due to sustained NFκB suppression. Drugs affecting induced, but not basal, NFκB activity may have the potential to provide therapeutic benefit without associated toxicity. NFκB activation by stress-inducible cell cycle inhibitor p21 was shown to be mediated by a p21-stimulated transcription-regulating kinase CDK8. CDK8 and its paralog CDK19, associated with the transcriptional Mediator complex, act as coregulators of several transcription factors implicated in cancer; CDK8/19 inhibitors are entering clinical development. Here we show that CDK8/19 inhibition by different small-molecule kinase inhibitors or shRNAs suppresses the elongation of NFκB-induced transcription when such transcription is activated by p21-independent canonical inducers, such as TNFα. On NFκB activation, CDK8/19 are corecruited with NFκB to the promoters of the responsive genes. Inhibition of CDK8/19 kinase activity suppresses the RNA polymerase II C-terminal domain phosphorylation required for transcriptional elongation, in a gene-specific manner. Genes coregulated by CDK8/19 and NFκB includeIL8,CXCL1, andCXCL2, which encode tumor-promoting proinflammatory cytokines. Although it suppressed newly induced NFκB-driven transcription, CDK8/19 inhibition in most cases had no effect on the basal expression of NFκB-regulated genes or promoters; the same selective regulation of newly induced transcription was observed with other transcription signals potentiated by CDK8/19. This selective role of CDK8/19 identifies these kinases as mediators of transcriptional reprogramming, a key aspect of development and differentiation as well as pathological processes.

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Section: Significancementioning

confidence: 99%

CDK8/19 Mediator kinases potentiate induction of transcription by NFκB

Chen

Liang

Jiang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

108

130

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“…CDK5 has been proposed to contribute to a variety of procancer functions, including cell migration, proliferation, and survival (Goodyear and Sharma, 2007;Demelash et al, 2012); maintenance of RasRal signaling (Feldmann et al, 2010); and promotion of the TGFb-induced epithelial to mesenchymal transition (Liang et al, 2013). Likewise, accumulating evidence indicates a role for CDK8 in some human cancers (Firestein et al, 2008;Gu et al, 2013;He et al, 2013;Li et al, 2014a,b,c;Xu et al, 2015). Fig.…”

Section: Non-cell Cycle Cdks As Drug Targetsmentioning

confidence: 99%

Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics

et al. 2015

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Cyclin-dependent kinases (CDKs) have been considered promising drug targets for a number of years, but most CDK inhibitors have failed rigorous clinical testing. Recent studies demonstrating clear anticancer efficacy and reduced toxicity of CDK4/6 inhibitors such as palbociclib and multi-CDK inhibitors such as dinaciclib have rejuvenated the field. Favorable results with palbociclib and its recent U.S. Food and Drug Administration approval demonstrate that CDK inhibitors with narrow selectivity profiles can have clinical utility for therapy based on individual tumor genetics. A brief overview of results obtained with ATPcompetitive inhibitors such as palbociclib and dinaciclib is presented, followed by a compilation of new avenues that have been pursued toward the development of novel, non-ATPcompetitive CDK inhibitors. These creative ways to develop CDK inhibitors are presented along with crystal structures of these agents complexed with CDK2 to highlight differences in their binding sites and mechanisms of action. The recent successes of CDK inhibitors in the clinic, combined with the potential for structure-based routes to the development of non-ATP-competitive CDK inhibitors, and evidence that CDK inhibitors may have use in suppressing chromosomal instability and in synthetic lethal drug combinations inspire optimism that CDK inhibitors will become important weapons in the fight against cancer.

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“…Most evidence has been gathered for the kinase module subunit CDK8, which has been linked to colon and pancreatic cancer (8,9) and was also investigated as a potential target in cancer therapy (10,11). Other subunits have also been reported in neoplastic conditions such as MED12 in uterine leiomyomas, fibroepithelial breast tumors, and prostate cancer (12)(13)(14), MED15 in prostate cancer and head and neck cancer (15,16), and cyclin C in acute lymphoblastic leukemia (17).…”

Section: Introductionmentioning

confidence: 99%

Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer

Brägelmann

Klümper²,

Offermann³

et al. 2016

Clinical Cancer Research

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Purpose: The Mediator complex is a multiprotein assembly, which serves as a hub for diverse signaling pathways to regulate gene expression. Because gene expression is frequently altered in cancer, a systematic understanding of the Mediator complex in malignancies could foster the development of novel targeted therapeutic approaches.Experimental Design: We performed a systematic deconvolution of the Mediator subunit expression profiles across 23 cancer entities (n ¼ 8,568) using data from The Cancer Genome Atlas (TCGA). Prostate cancer-specific findings were validated in two publicly available gene expression cohorts and a large cohort of primary and advanced prostate cancer (n ¼ 622) stained by immunohistochemistry. The role of CDK19 and CDK8 was evaluated by siRNA-mediated gene knockdown and inhibitor treatment in prostate cancer cell lines with functional assays and gene expression analysis by RNAseq.Results: Cluster analysis of TCGA expression data segregated tumor entities, indicating tumor-type-specific Mediator complex compositions. Only prostate cancer was marked by high expression of CDK19. In primary prostate cancer, CDK19 was associated with increased aggressiveness and shorter disease-free survival. During cancer progression, highest levels of CDK19 and of its paralog CDK8 were present in metastases. In vitro, inhibition of CDK19 and CDK8 by knockdown or treatment with a selective CDK8/CDK19 inhibitor significantly decreased migration and invasion.Conclusions: Our analysis revealed distinct transcriptional expression profiles of the Mediator complex across cancer entities indicating differential modes of transcriptional regulation. Moreover, it identified CDK19 and CDK8 to be specifically overexpressed during prostate cancer progression, highlighting their potential as novel therapeutic targets in advanced prostate cancer.

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Mutated K-ras activates CDK8 to stimulate the epithelial-to-mesenchymal transition in pancreatic cancer in part via the Wnt/β-catenin signaling pathway

Cited by 113 publications

References 52 publications

CDK8/19 Mediator kinases potentiate induction of transcription by NFκB

CDK8/19 Mediator kinases potentiate induction of transcription by NFκB

Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics

Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer

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