CDK8 maintains tumor dedifferentiation and embryonic stem cell pluripotency

Adam S. Adler, Mark L. McCleland, Tom Truong, Shari Lau, Zora Modrusan, Tim M. Soukup, Merone Roose-Girma, Elizabeth M. Blackwood, Ron Firestein

Research output: Contribution to journalArticleResearchpeer-review

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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 stemcell 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 stemcells 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 stemcellMYCtarget 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 stemcells in an undifferentiated state. This raises the intriguing possibility that targeting CDK8 therapeuticallymay specifically inhibit the stem-like properties of cancer cells.

Original languageEnglish
Pages (from-to)2129-2139
Number of pages11
JournalCancer Research
Volume72
Issue number8
DOIs
Publication statusPublished - 15 Apr 2012
Externally publishedYes

Cite this

Adler, A. S., McCleland, M. L., Truong, T., Lau, S., Modrusan, Z., Soukup, T. M., ... Firestein, R. (2012). CDK8 maintains tumor dedifferentiation and embryonic stem cell pluripotency. Cancer Research, 72(8), 2129-2139. https://doi.org/10.1158/0008-5472.CAN-11-3886
Adler, Adam S. ; McCleland, Mark L. ; Truong, Tom ; Lau, Shari ; Modrusan, Zora ; Soukup, Tim M. ; Roose-Girma, Merone ; Blackwood, Elizabeth M. ; Firestein, Ron. / CDK8 maintains tumor dedifferentiation and embryonic stem cell pluripotency. In: Cancer Research. 2012 ; Vol. 72, No. 8. pp. 2129-2139.
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Adler, AS, McCleland, ML, Truong, T, Lau, S, Modrusan, Z, Soukup, TM, Roose-Girma, M, Blackwood, EM & Firestein, R 2012, 'CDK8 maintains tumor dedifferentiation and embryonic stem cell pluripotency', Cancer Research, vol. 72, no. 8, pp. 2129-2139. https://doi.org/10.1158/0008-5472.CAN-11-3886

CDK8 maintains tumor dedifferentiation and embryonic stem cell pluripotency. / Adler, Adam S.; McCleland, Mark L.; Truong, Tom; Lau, Shari; Modrusan, Zora; Soukup, Tim M.; Roose-Girma, Merone; Blackwood, Elizabeth M.; Firestein, Ron.

In: Cancer Research, Vol. 72, No. 8, 15.04.2012, p. 2129-2139.

Research output: Contribution to journalArticleResearchpeer-review

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Adler AS, McCleland ML, Truong T, Lau S, Modrusan Z, Soukup TM et al. CDK8 maintains tumor dedifferentiation and embryonic stem cell pluripotency. Cancer Research. 2012 Apr 15;72(8):2129-2139. https://doi.org/10.1158/0008-5472.CAN-11-3886