title: CDK8 maintains tumor dedifferentiation and embryonic stem cell pluripotency.
abstract: CDK8 is a cyclin-dependent kinase that mediates transcriptional control of pathways linked to both cancer and stem cells. In this study, we show that CDK8 is required for both tumor growth and maintenance of tumor dedifferentiation in vivo and uncover a common role for CDK8 in controlling cancer and stem cell function. Acute CDK8 loss in vivo strongly inhibited tumor growth and promoted differentiation. Transcriptional profiling identified a set of embryonic stem cell-related genes that are activated by CDK8 in cancer. Consistent with this, we found that CDK8 expression correlated to the embryonic stem cell pluripotency state and loss of CDK8 caused embryonic stem cells to differentiate. This effect was, at least partially, mediated by the ability of CDK8 to regulate MYC protein and downstream MYC target gene expression. Similar regulation of MYC target genes by CDK8 was observed in colon tumor cells, and increased expression of a CDK8-regulated, embryonic stem cell MYC target gene signature was associated with loss of differentiation and poor outcome in primary human colon cancers. Together, these observations reveal that CDK8 acts, at least in part, through MYC to maintain both tumors and embryonic stem cells in an undifferentiated state. This raises the intriguing possibility that targeting CDK8 therapeutically may specifically inhibit the stem-like properties of cancer cells.
authors.affiliation: Department of Pathology, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Adler
authors.forename: Mark L
authors.initials: ML
authors.lastname: McCleland
authors.forename: Tom
authors.initials: T
authors.lastname: Truong
authors.forename: Shari
authors.initials: S
authors.lastname: Lau
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Tim M
authors.initials: TM
authors.lastname: Soukup
authors.forename: Merone
authors.initials: M
authors.lastname: Roose-Girma
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Blackwood
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054337:Cell Dedifferentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D002469:Cell Separation; D056850:Cyclin-Dependent Kinase 8 / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000201:enzymology*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D016259:Genes, myc; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009374:Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000201:enzymology*; D014162:Transfection
chemical_list: C095686:CDK8 protein, human; D056850:Cyclin-Dependent Kinase 8