PUBLICATION
p38 MAPK-dependent phosphorylation of transcription factor SOX2 promotes an adaptive response to BRAF inhibitors in melanoma cells
- Authors
- Pietrobono, S., De Paolo, R., Mangiameli, D., Marranci, A., Battisti, I., Franchin, C., Arrigoni, G., Melisi, D., Poliseno, L., Stecca, B.
- ID
- ZDB-PUB-220810-7
- Date
- 2022
- Source
- The Journal of biological chemistry 298(9): 102353 (Journal)
- Registered Authors
- Keywords
- BRAF inhibitor, SOX2, drug resistance, p38 MAPK
- MeSH Terms
-
- Phosphorylation
- Proto-Oncogene Proteins B-raf*/metabolism
- Adenosine Triphosphate/metabolism
- Drug Resistance, Neoplasm
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/therapeutic use
- Melanoma*/drug therapy
- Melanoma*/genetics
- Melanoma*/metabolism
- p38 Mitogen-Activated Protein Kinases/genetics
- p38 Mitogen-Activated Protein Kinases/metabolism
- Humans
- Zebrafish/metabolism
- Animals
- MAP Kinase Signaling System
- Cell Line, Tumor
- SOXB1 Transcription Factors/genetics
- SOXB1 Transcription Factors/metabolism
- PubMed
- 35944584 Full text @ J. Biol. Chem.
Citation
Pietrobono, S., De Paolo, R., Mangiameli, D., Marranci, A., Battisti, I., Franchin, C., Arrigoni, G., Melisi, D., Poliseno, L., Stecca, B. (2022) p38 MAPK-dependent phosphorylation of transcription factor SOX2 promotes an adaptive response to BRAF inhibitors in melanoma cells. The Journal of biological chemistry. 298(9):102353.
Abstract
Despite recent advances in the development of BRAF kinase inhibitors (BRAFi) for BRAF-mutant melanomas, development of resistance remains a major clinical problem. In addition to genetic alterations associated with intrinsic resistance, several adaptive response mechanisms are known to be rapidly activated to allow cell survival in response to treatment, limiting efficacy. A better understanding of the mechanisms driving resistance is urgently needed to improve the success of BRAF-targeted therapies and to make therapeutic intervention more durable. In this study we identify the mitogen-activated protein kinase (MAPK) p38 as a novel mediator of the adaptive response of melanoma cells to BRAF-targeted therapy. Our findings demonstrate that BRAFi leads to an early increase in p38 activation, which promotes phosphorylation of the transcription factor SOX2 at Ser251, enhancing SOX2 stability, nuclear localization, and transcriptional activity. Furthermore, functional studies show that SOX2 depletion increases sensitivity of melanoma cells to BRAFi, whereas overexpression of a phosphomimetic SOX2-S251E mutant is sufficient to drive resistance and desensitize melanoma cells to BRAFi in vitro and in a Zebrafish xenograft model. We also found that SOX2 phosphorylation at serine 251 confers resistance to BRAFi by binding to the promoter and increasing transcriptional activation of the ATP-binding cassette (ABC) drug efflux transporter ABCG2. In summary, we unveil a p38/SOX2-mediated mechanism of adaptive response to BRAFi, which provides pro-survival signals to melanoma cells against the cytotoxic effects of BRAFi prior to acquiring resistance.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping