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CDK7 and MITF repress a transcription program involved in survival and drug tolerance in melanoma

Pietro Berico1,2,3,4, Max Cigrang1,2,3,4, Guillaume Davidson1,2,3,4

  • 1Institut de Génétique et de Biologie Moléculaire et Cellulaire, Equipe Labélisée Ligue contre le Cancer, Strasbourg, France.

EMBO Reports
|July 23, 2021
PubMed

Insights

Chronic inhibition of Cyclin-Dependent Kinase 7 (CDK7) triggers melanoma dedifferentiation, promoting metastasis and drug resistance. This involves a GATA6-driven gene program, highlighting CDK7

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Melanoma cell plasticity, switching between melanocytic and mesenchymal states, is a key driver of metastasis and therapeutic resistance.
  • Cyclin-Dependent Kinase 7 (CDK7), a component of the general transcription factor TFIIH, plays a role in regulating gene expression.

Purpose of the Study:

  • To investigate the role of CDK7 in melanoma cell phenotype switching.
  • To elucidate the molecular mechanisms by which CDK7 inhibition affects melanoma dedifferentiation, drug tolerance, and metastasis.
  • To identify key transcription factors and gene expression programs involved in CDK7-mediated melanoma plasticity.

Main Methods:

  • Utilized chronic CDK7 inhibition in melanoma cell models.
  • Analyzed gene expression profiles to identify mesenchymal-type signatures and GATA6-dependent programs.
  • Investigated the interaction between MITF (melanocyte master regulator) and GATA6.
  • Examined GATA6 expression in patient-derived xenografts with low MITF levels.

Main Results:

  • Chronic CDK7 inhibition induced dedifferentiation of melanocytic melanoma cells into a mesenchymal-like state.
  • This dedifferentiation was associated with acquired tolerance to targeted therapies.
  • A GATA6-dependent gene expression program, including AMIGO2 and ABCG2, was identified, contributing to melanoma survival and drug tolerance.
  • CDK7 promotes MITF expression, which represses GATA6 in melanocytic cells.
  • GATA6 expression was upregulated in MITF-low melanoma cells from patient-derived xenografts.

Conclusions:

  • CDK7 inhibition is a critical regulator of melanoma dedifferentiation, driving a mesenchymal phenotype.
  • The study reveals a novel molecular cascade involving MITF repression of GATA6, leading to the activation of survival and drug resistance pathways.
  • Targeting the CDK7-MITF-GATA6 axis may offer new therapeutic strategies for overcoming melanoma metastasis and drug resistance.
Keywords:
CDK7GATA6MITFTFIIHmelanoma

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