CDK9 is necessary for the proliferation and maintenance of MYC-driven hepatocellular carcinoma.

  • Major finding: CDK9 is necessary for the proliferation and maintenance of MYC-driven hepatocellular carcinoma.

  • Mechanism: MYC-driven proliferation requires CDK9-mediated transcription elongation of MYC target genes.

  • Impact: CDK9 may serve as a therapeutic target in a subset of MYC-overexpressing tumors.

Hepatocellular carcinoma (HCC) is an aggressive and deadly disease with a one-year survival rate of less than 50%, underscoring the need to identify effective targeted therapies. The MYC oncogene drives tumor proliferation in multiple cancer types, including HCC, by regulating gene transcription, protein translation, and DNA replication; however, therapeutic strategies to target MYC have thus far been unsuccessful. Huang, Lujambio, and colleagues applied a custom shRNA library to a MYC-driven murine HCC model in order to identify candidate drug targets that are necessary to sustain the addiction of HCC cells to MYC. Among the top candidates, depletion of cyclin-dependent kinase 9 (CDK9), which stimulates transcription elongation by RNA polymerase II, significantly decreased HCC cell proliferation. This effect was reproducible across several murine and human HCC cell lines and was specific to MYC-overexpressing cells, suggesting that CDK9 is critical for the growth of MYC-driven HCC. This idea was further supported pharmacologically, as disruption of CDK9 activity with the kinase inhibitor PHA-767491 reduced the proliferative capacity of several HCC cell lines, similar to CDK9 knockdown. MYC expression levels positively correlated with sensitivity to CDK9 inhibition, and gene expression in inhibitor-sensitive cells was enriched for MYC-dependent transcriptional signatures. CDK9 mediated the transcription elongation of multiple MYC target genes in MYC-overexpressing HCC cells, demonstrating the dependence of MYC-driven tumors on CDK9 activity. Consistent with this notion, forced overexpression of MYC in low MYC–expressing cells increased the transcription elongation of MYC-dependent genes and conferred sensitivity to CDK9 inhibition. Furthermore, silencing of CDK9 impaired MYC-driven tumor formation and inhibited the growth of established murine liver tumors and human HCC xenografts, establishing an essential role for CDK9 and transcription elongation in MYC-mediated oncogenesis. These results suggest CDK9 as a potential therapeutic target for the treatment of MYC-addicted cancers.

Huang CH, Lujambio A, Zuber J, Tschaharganeh DF, Doran MG, Evans MJ, et al.CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. Genes Dev 2014;280:1800–14.

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