Fig. 7: Working model of CHOP-dependent IL-8 regulation, after dabrafenib and trametinib treatment, according to BRAF status.
a Upon addition of the BRAF inhibitor dabrafenib, signaling output from BRAFV600E is blocked and there is a transient suppression of ERK activation and MAPK signaling. In this genetic context, CHOP is exported to the cytoplasmic compartment, thus resulting in the downregulation of IL-8. b In contrast, in BRAF-wt contexts, even in the presence of dabrafenib, BRAF forms a complex with CRAF and hyperactivates CRAF itself, thereby driving paradoxical hyper-activation of both MEK and ERK. Due to CHOP nuclear import and histone acetylation, chromatin is accessible to CHOP, thereby increasing its binding to the IL-8 promoter, resulting in IL-8 transcription and protein production. c Trametinib inhibits MEK activity, thereby downregulating p-ERK levels: CHOP translocates from the nucleus to the cytosol and IL-8 gene is not transcribed, regardless of BRAF genetic status.
