TFIIH kinase CDK7 antagonizes phenotype switching and emergence of drug tolerance in melanoma
Berico, P.; cigrang, m.; Braun, C.; Davidson, G.; Sandoz, j.; Legras, S.; peyresaubes, F.; Robles, C. G.; egly, j.-m.; compe, e.; Davidson, I.; Coin, F.
Show abstract
Melanoma cells switch back-and-forth between phenotypes of proliferation and invasion in response to changing microenvironment, driving metastatic progression. We show that inhibition of the TFIIH kinase CDK7 (CDK7i) results in a melanocytic to mesenchymal phenotype switching and acquisition of targeted therapy tolerance. We identify a gene expression program controlled by the transcription factor GATA6, which participates in drug tolerance in mesenchymal-like cells and which is antagonized by CDK7 in melanocytic-like cells. This program emerges concomitantly with loss of melanocyte lineage-specific MITF protein following CDK7i. By dissecting the underlying mechanism, we observe that CDK7 accumulates at the super-enhancer regulating MITF to drive its expression. MITF itself binds to a intronic region of GATA6 to transcriptionally repress it. This molecular cascade antagonizes expression of the GATA6 regulon that only emerges in MITF-low cells of metastatic melanoma. Our work reveals a role for CDK7 in counteracting phenotype switching and activation of a gene expression program mediating multidrug tolerance in melanoma cells.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Super-enhancer driven expression of BAHCC1 promotes melanomacell proliferation and genome stability 97%
- AP-1 transcription factor network explains diverse patterns of cellular plasticity in melanoma cells 97%
- PRMT7 ablation stimulates anti-tumor immunity and sensitizes melanoma to immune checkpoint blockade 97%
Similar papers in this journal
- Cancer-associated fibroblasts exert a pro-angiogenic activity in Merkel cell carcinoma 93%
- YAP1-TAZ/TEAD transcriptional networks restrain differentiation downstream of oncogenic Hedgehog-SMO activity 93%
- Epidermal loss of PRMT5 leads to the emergence of an atypical basal keratinocyte-like cell population and defective skin stratification 93%
Similar papers in this journal
- RIPOR2 promotes multinucleation of melanoma cells downstream of the RAS/ERK oncogenic pathway 94%
- Systems-level network modeling deciphers the master regulators of phenotypic plasticity and heterogeneity in melanoma 94%
- A Non-genetic Mechanism for Chemoresistance in Lung Cancer: The Role of Integrin β4/Paxillin Axis 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.