CDK7 and MITF repress a transcription program involved in survival and drug tolerance in melanoma. (23rd July 2021)

• Record Type: Journal Article
• Authors: Berico, Pietro; Cigrang, Max; Davidson, Guillaume; Braun, Cathy; Sandoz, Jeremy; Legras, Stephanie; Vokshi, Bujamin Hektor; Slovic, Nevena; Peyresaubes, François; Gene Robles, Carlos Mario; Egly, Jean‐Marc; Compe, Emmanuel; Davidson, Irwin; Coin, Frederic
• Is Part Of: EMBO reports. Volume 22:Number 9(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-07-23
• Subjects: CDK7 -- TFIIH -- MITF -- melanoma -- GATA6; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202051683
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: 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. Synopsis: The repressive function of the melanocyte lineage transcription factor MITF participates in a molecular cascade, involving the CDK7 kinase, regulating the activation of a transcriptional program involved in survival and drug resistance of melanoma cells. Inhibition of CDK7 induces dedifferentiation of proliferative melanoma cells and tolerance to targeted therapies. Dedifferentiated cells show GATA6‐dependent gene expression promoting melanoma survival or drug tolerance. CDK7 drives expression of MITF that binds to an intron of GATA6 to repress its expression in melanocytic‐type cells. Abstract : The repressive function of the melanocyte lineage transcription factor MITF participates in a molecular cascade, involving the CDK7 kinase, regulating the activation of a transcriptional program involved in survival and drug resistance of melanoma cells.