CDK8 expression in 470 colorectal cancers in relation to β-catenin activation, other molecular alterations and patient survival

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
International Journal of Cancer (Impact Factor: 5.09). 06/2010; 126(12):2863-73. DOI: 10.1002/ijc.24908
Source: PubMed


Alterations in the Wnt/beta-catenin pathway define a key event in the pathogenesis of colon cancer. We have recently shown that CDK8, the gene encoding a cyclin-dependent kinase (CDK) component of the Mediator complex, acts as a colon cancer oncogene that is necessary for beta-catenin activity. Here, we tested the hypothesis that colorectal cancers with CDK8 expression have distinct clinical, prognostic and molecular attributes. Among 470 colorectal cancers identified in 2 prospective cohort studies, CDK8 expression was detected in 329 (70%) tumors by immunohistochemistry. Cox proportional hazards model and backward stepwise elimination were used to compute hazard ratio (HR) of deaths according to CDK8 status, initially adjusted for various patient and molecular features, including beta-catenin, p53, p21, p27 (CDK inhibitors), cyclin D1, fatty acid synthase (FASN), cyclooxygenase-2 (COX-2), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), LINE-1 methylation, and mutations in KRAS, BRAF and PIK3CA. CDK8 expression in colorectal cancer was independently associated with beta-catenin activation (p = 0.0002), female gender (p < 0.0001) and FASN overexpression (p = 0.0003). Among colon cancer patients, CDK8 expression significantly increased colon cancer-specific mortality in both univariate analysis [HR 1.70; 95% confidence interval (CI), 1.03-2.83; p = 0.039] and multivariate analysis (adjusted HR 2.05; 95% CI, 1.18-3.56; p = 0.011) that was adjusted for potential confounders including beta-catenin, COX-2, FASN, LINE-1 hypomethylation, CIMP and MSI. CDK8 expression was unrelated with clinical outcome among rectal cancer patients. These data support a potential link between CDK8 and beta-catenin, and suggest that CDK8 may identify a subset of colon cancer patients with a poor prognosis.

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Available from: Katsuhiko Nosho
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    • "These structural data will be useful for generating small molecules that could bind key control points within Mediator. A particularly promising therapeutic target is CDK8 (Xu & Ji, 2011), which is a potent oncogene (Firestein et al., 2008; Kapoor et al., 2010; Morris et al., 2008) whose expression is associated with poor clinical outcomes (Firestein et al., 2010; Nagalingam et al., 2012; Porter et al., 2012). In mammals, CDK8 function can maintain tumors and stem cells in an undifferentiated state (Adler et al., 2012) and can promote cell growth via the serum response pathway (Donner et al., 2010). "
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    ABSTRACT: Abstract The Mediator complex is a multi-subunit assembly that appears to be required for regulating expression of most RNA polymerase II (pol II) transcripts, which include protein-coding and most non-coding RNA genes. Mediator and pol II function within the pre-initiation complex (PIC), which consists of Mediator, pol II, TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH and is approximately 4.0 MDa in size. Mediator serves as a central scaffold within the PIC and helps regulate pol II activity in ways that remain poorly understood. Mediator is also generally targeted by sequence-specific, DNA-binding transcription factors (TFs) that work to control gene expression programs in response to developmental or environmental cues. At a basic level, Mediator functions by relaying signals from TFs directly to the pol II enzyme, thereby facilitating TF-dependent regulation of gene expression. Thus, Mediator is essential for converting biological inputs (communicated by TFs) to physiological responses (via changes in gene expression). In this review, we summarize an expansive body of research on the Mediator complex, with an emphasis on yeast and mammalian complexes. We focus on the basics that underlie Mediator function, such as its structure and subunit composition, and describe its broad regulatory influence on gene expression, ranging from chromatin architecture to transcription initiation and elongation, to mRNA processing. We also describe factors that influence Mediator structure and activity, including TFs, non-coding RNAs and the CDK8 module.
    Full-text · Article · Oct 2013 · Critical Reviews in Biochemistry and Molecular Biology
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    • "Pyro 388 N Y [62] Pyro 470 N Y [70] Pyro 182 N Y [71] Pyro 10 N Y [44] Pyro 765 N Y [72] Pyro 1113 N Y [45] Pyro 869 N Y [73] Pyro 643 N Y [61] Pyro 60 N Y [31] Pyro 22 N Y [74] Pyro 95 N Y [75] Pyro 161 N Y [46] Pyro 252 N Y [48] SB 19 N Y [76] qPCR 205 N Y [77] COBRA 7 Y Y [50] COBRA 18 N Y [26] COBRA 80 N Y [78] COBRA 39 N Y [79] MSP 155 Y Y [80] Prostate COBRA 179 N Y [63] COBRA 99 N Y [64] Y in 49% [56] SB 64 N Y [65] SB 50 Y Y in 34% [69] SB 50 N Y in 31% [66] SB 14 Y Y [68] COMPARE 1 116 Y Y [67] COBRA 7 Y Y [50] "

    Full-text · Dataset · Jun 2013
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    • "The expression of CDK8 is significantly higher in samples from women than from men but is not correlated with tumor stage, body-mass index, or age of patients at diagnosis (Firestein et al., 2010). At the molecular level, CDK8 expression is correlated with high b-catenin activation, expression of tumor suppressor p53, and overexpression of FASN (fatty acid synthase ), suggesting that CDK8 activity may regulate multiple pathways involved in colorectal tumorigenesis (Firestein et al., 2010). The potential link between CDK8 and b-catenin is also supported by an independent study with 127 cases of colorectal adenocarcinoma patients (Seo et al., 2010). "
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    ABSTRACT: Appropriately controlled gene expression is fundamental for normal growth and survival of all living organisms. In eukaryotes, the transcription of protein-coding mRNAs is dependent on RNA polymerase II (Pol II). The multi-subunit transcription cofactor Mediator complex is proposed to regulate most, if not all, of the Pol II-dependent transcription. Here we focus our discussion on two subunits of the Mediator complex, cyclin-dependent kinase 8 (CDK8) and its regulatory partner Cyclin C (CycC), because they are either mutated or amplified in a variety of human cancers. CDK8 functions as an oncoprotein in melanoma and colorectal cancers, thus there are considerable interests in developing drugs specifically targeting the CDK8 kinase activity. However, to evaluate the feasibility of targeting CDK8 for cancer therapy and to understand how their dysregulation contributes to tumorigenesis, it is essential to elucidate the in vivo function and regulation of CDK8-CycC, which are still poorly understood in multi-cellular organisms. We summarize the evidence linking their dysregulation to various cancers and present our bioinformatics and computational analyses on the structure and evolution of CDK8. We also discuss the implications of these observations in tumorigenesis. Because most of the Mediator subunits, including CDK8 and CycC, are highly conserved during eukaryotic evolution, we expect that investigations using model organisms such as Drosophila will provide important insights into the function and regulation of CDK8 and CycC in different cellular and developmental contexts.
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