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Linking cancer transcriptional addictions by CDK7 to YAP/TAZ

Stefano Piccolo1

  • 1Department of Molecular Medicine, University of Padua School of Medicine, 35121 Padua, Italy; IFOM, The FIRC Institute of Molecular Oncology, 35121 Padua, Italy piccolo@bio.unipd.it.

Genes & Development
|January 4, 2020
PubMed

Insights

Cyclin-dependent kinase 7 (CDK7) inhibition shows cancer therapy potential. New research reveals CDK7 directly phosphorylates YAP/TAZ/Yki coactivators, promoting their oncogenic activity independently of the Hippo pathway.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Cyclin-dependent kinase 7 (CDK7) is primarily known for its role in RNA polymerase II (Pol II) transcription.
  • The precise function of CDK7 in specific transcriptional programs driving tumor cell proliferation remains incompletely understood.
  • Reconciling CDK7's basal transcriptional roles with its function in tumor-specific programs is crucial for targeted cancer therapies.

Purpose of the Study:

  • To investigate the role of CDK7 in regulating oncogenic coactivators YAP/TAZ/Yki.
  • To elucidate the mechanism by which CDK7 influences the stability and activity of YAP/TAZ/Yki.
  • To determine if CDK7's function in this context is linked to its known roles in basal transcription or the Hippo pathway.

Main Methods:

  • Utilized molecular biology techniques to study CDK7 activity and its interaction with YAP/TAZ/Yki.
  • Employed biochemical assays to assess phosphorylation, ubiquitination, and protein degradation.
  • Investigated signaling pathways, including the Hippo cascade, in relation to CDK7 function.

Main Results:

  • Demonstrated that CDK7 directly phosphorylates YAP/TAZ/Yki in the nucleus.
  • Showed that CDK7-mediated phosphorylation protects YAP/TAZ/Yki from ubiquitination and subsequent degradation.
  • Found this mechanism to be independent of the canonical Hippo signaling pathway and CDK7's basal transcriptional functions.

Conclusions:

  • CDK7 directly promotes the oncogenic activity of YAP/TAZ/Yki coactivators through nuclear phosphorylation.
  • This newly identified function of CDK7 is independent of its established roles in basal transcription and the Hippo pathway.
  • Targeting CDK7 may represent a novel therapeutic strategy for cancers driven by YAP/TAZ/Yki activity.
Keywords:
CDK3CRL4Cul4DCAF12HippoTazYapYkicancerorgan size

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