Studies by two groups converged to implicate the cyclin-dependent kinase CDK8 in the pathogenesis of colorectal cancer, with one also revealing that CDK8 provides an unexpected link between two signaling pathways. Wnt signaling, which is critical in normal development, leads to translocation to the nucleus of β-catenin, and thereby the activation of target genes. Noting that aberrant activation of Wnt-β-catenin signaling drives tumorigenesis in nearly all colorectal cancers, Firestein et al. conducted separate screens of human colon cancer cells for genes required for β-catenin activity and genes required for proliferation. Of 1000 genes screened, nine were implicated in both processes and, of these nine, only CDK8 was located in a chromosomal region commonly amplified in colon cancer. CDK8 was overexpressed in a subset of colon cancer cells, and overexpression of wild-type CDK8—but not a kinase-dead mutant—led to transformation of NIH 3T3 cells. Indeed, kinase-dead CDK8 inhibited β-catenin-driven cell transformation. CDK8 suppression with shRNA inhibited proliferation of colon cancer cell lines overexpressing CDK8 and inhibited β-catenin-dependent transcription and the expression of several β-catenin targets implicated in cancer, including MYC. CDK8 bound to the MYC promoter, and its knockdown reduced the amount of β-catenin bound to the MYC promoter. Thus, the authors conclude that CDK8 is an oncogene and that its overexpression can contribute to colorectal cancer, at least in part by promoting β-catenin signaling.
Morris et al. found that overexpression of Drosophila β-catenin (Arm) suppressed an apoptotic wing phenotype caused by increased expression of E2F1 [a transcription factor that is a target of inhibition by the retinoblastoma tumor suppressor protein (pRB)]; analyses of various genetic interactions confirmed a functional antagonism between Drosophila E2F1 and Arm signaling. Furthermore, E2F1 inhibited transcriptional activation of a reporter by a stable form of β-catenin in an Rb-deficient human cell line (Saos2 cells), inhibited MYC expression in Saos2 and colorectal cancer cells, and elicited an eventual increase in β-catenin degradation. RB1 is rarely mutated in colorectal cancer and, intriguingly, its knockdown with shRNA led to inhibition of β-catenin activity and proliferation of a colorectal cancer cell line. A Drosophila screen for genes that inhibit E2F1 activity identified fly CDK8, an interaction confirmed by RNAi-mediated CDK8 depletion. Drosophila CDK8 and E2F1 interacted in a pull-down assay and human CDK8 coimmunoprecipitated with and phosphorylated E2F1. Chromatin immunoprecipitation indicated that both CDK8 and E2F1were present at the MYC promoter; moreover, CDK8 suppressed E2F1-dependent inhibition of β-catenin-mediated transcription. Thus, inhibition of E2F1 provides another mechanism whereby CDK8 promotes β-catenin signaling and, in colorectal cancer, pRB appears to promote—rather than inhibit—tumorigenesis. Bernards provides thoughtful commentary on both papers.
R. Firestein, A. J. Bass, S. Y. Kim, I. F. Dunn, S. J. Silver, I. Guney, E. Freed, A. H. Ligon, N. Vena, S. Ogino, M. G. Chheda, P. Tamayo, S. Finn, Y. Shrestha, J. S. Boehm, S. Jain, E. Bojarski, C. Mermel, J. Barretina, J. A. Chan, J. Baselga, J. Tabernero, D. E. Root, C. S. Fuchs, M. Loda, R. A. Shivdasani, M. Meyerson, W. C. Hahn, CDK8 is a colorectal cancer oncogene that regulates β-catenin activity. Nature 455, 547-551 (2008). [PubMed]
E. J. Morris, J.-Y. Ji, F. Yang, L. Di Stefano, A. Herr, N.-S. Moon, E.-J. Kwon, K. M. Haigis, A. M. Näär, N. J. Dyson, E2F1 represses β-catenin transcription and is antagonized by both pRB and CDK8. Nature 455, 552-556 (2008). [PubMed]
R. Bernards, Entangled pathways. Nature 455, 479-480 (2008). [PubMed]