CDK8 is a colorectal cancer oncogene that regulates β-catenin activity

By R. Firestein, A. Bass, S. Kim, I. Dunn, S. Silver, Isil Guney, E. Freed, A. Ligon, Natalie Vena, S. Ogino and 18 more. Nature, 2008

705 citations recorded by the source corpus.

Aberrant activation of the canonical WNT/β-catenin pathway occurs in almost all colorectal cancers and contributes to their growth, invasion and survival. Although dysregulated β-catenin activity drives colon tumorigenesis, further genetic perturbations are required to elaborate full malignant transformation. To identify genes that both modulate β-catenin activity and are essential for colon cancer cell proliferation, we conducted two loss-of-function screens in human colon cancer cells and compared genes identified in these screens with an analysis of copy number alterations in colon cancer specimens. One of these genes, CDK8, which encodes a member of the mediator complex, is located at 13q12.13, a region of recurrent copy number gain in a substantial fraction of colon cancers. Here we show that the suppression of CDK8 expression inhibits proliferation in colon cancer cells characterized by high levels of CDK8 and β-catenin hyperactivity. CDK8 kinase activity was necessary for β-catenin-driven transformation and for expression of several β-catenin transcriptional targets. Together these observations suggest that therapeutic interventions targeting CDK8 may confer a clinical benefit in β-catenin-driven malignancies.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/ded02f2f4178eddde108674e24a4a82fc362ea47

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Marcos Malumbres
2. Philipp Kaldis
3. Yanqin Zuo
4. Craig H. Mermel
5. L. Yao
6. Yitian Wang
7. Gad Getz
8. L. Ye

In Oncology

1. Marcos Malumbres
2. Philipp Kaldis
3. Gad Getz
4. Richard A. Young

Citations in the corpus

• Wnt/β-catenin signaling in cancers and targeted therapies (2021, background): “Thus, CDK8 may be a promising target for β-catenin-associated cancers.(246) The translationally controlled tumor protein (TCTP) can enhance the transcription complex activity by increasing the ability of β-catenin–Tcf binding and then inducing the growth of glioma tumor.”
• CDK8/9 drive Smad transcriptional action, turnover and YAP interactions in BMP and TGFβ pathways (2009, neutral): “CDK8 phosphorylates the C-terminal domain (CTD) of RNAP II and certain enhancer-binding transcription factors (Donner et al., 2007; Firestein et al., 2008; Morris et al., 2008).”
• Transcriptional Regulation and its Misregulation in Disease (2013, neutral): “MED12 is part of the CDK module of the Mediator complex, and the CDK8 subunit of this module has been reported to act as an oncogene in both colon cancer and melanoma (Firestein et al., 2008; Kapoor et al., 2010; Morris et al., 2008).”
• Control of Embryonic Stem Cell State (2011, background): “…been associated with Opitz-Kaveggia (FG) syndrome, Lujan syndrome, schizophrenia, Transposition of the Great Arteries (TGA) syndrome, and colon cancer progression (Ding et al., 2008; Firestein et al., 2008; Muncke et al., 2003; Philibert and Madan, 2007; Risheg et al., 2007; Schwartz et al., 2007).”
• Cyclin-dependent kinases (2014, background): “Cdk8 exhibits copy-number gains in colon cancers, and recently it has been characterized as a coactivator of the beta-catenin pathway in colon cancer cell proliferation [60,61].”
• Cdks, cyclins and CKIs: roles beyond cell cycle regulation (2013, background): “An RNAi screen to identify modifiers of β-catenin transcriptional activity and colon cancer cell proliferation pinpointed CDK8 as a key player and demonstrated its copy number amplification in a substantial fraction of colorectal cancers (Firestein et al., 2008).”
• GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers (2011, methodology): “GISTIC has been applied to multiple cancer types, including glioblastoma [10,15], lung adenocarcinoma [16], melanoma [17], colorectal carcinoma [18], hepatocellular carcinoma [19], ovarian carcinoma [20], medulloblastoma [21], and lung and esophageal squamous carcinoma [22], and has helped identify ”
• Emerging roles of E2Fs in cancer: an exit from cell cycle control (2009, neutral): “It has been suggested that oncogene-stimulated proliferation may result in the need for a specific CDK family member, as seems to occur with CDK8 in colorectal cance”