CDK7 and MITF repress a transcription program involved in survival and drug tolerance in melanoma.
CDK7
GATA6
MITF
TFIIH
melanoma
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
06 09 2021
06 09 2021
Historique:
revised:
18
06
2021
received:
07
09
2020
accepted:
25
06
2021
pubmed:
24
7
2021
medline:
1
6
2022
entrez:
23
7
2021
Statut:
ppublish
Résumé
Melanoma cell phenotype switching between differentiated melanocytic and undifferentiated mesenchymal-like states drives metastasis and drug resistance. CDK7 is the serine/threonine kinase of the basal transcription factor TFIIH. We show that dedifferentiation of melanocytic-type melanoma cells into mesenchymal-like cells and acquisition of tolerance to targeted therapies is achieved through chronic inhibition of CDK7. In addition to emergence of a mesenchymal-type signature, we identify a GATA6-dependent gene expression program comprising genes such as AMIGO2 or ABCG2 involved in melanoma survival or targeted drug tolerance, respectively. Mechanistically, we show that CDK7 drives expression of the melanocyte lineage transcription factor MITF that in turn binds to an intronic region of GATA6 to repress its expression in melanocytic-type cells. We show that GATA6 expression is activated in MITF-low melanoma cells of patient-derived xenografts. Taken together, our data show how the poorly characterized repressive function of MITF in melanoma participates in a molecular cascade regulating activation of a transcriptional program involved in survival and drug resistance in melanoma.
Identifiants
pubmed: 34296805
doi: 10.15252/embr.202051683
pmc: PMC8419699
doi:
Substances chimiques
MITF protein, human
0
Microphthalmia-Associated Transcription Factor
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e51683Informations de copyright
© 2021 The Authors.
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