Oncogenic BRAF and p53 Interplay in Melanoma Cells and the Effects of the HDAC Inhibitor ITF2357 (Givinostat)

Oncogenic BRAF mutations are frequently observed in melanomas and are known to drive tumor progression and resistance to chemotherapy. Previous studies have demonstrated that the HDAC inhibitor ITF2357 (Givinostat) targets oncogenic BRAF in SK-MEL-28 and A375 melanoma cells. This study reveals that oncogenic BRAF localizes to the nucleus in these cells, and ITF2357 reduces BRAF levels in both nuclear and cytosolic compartments. Although p53 mutations are less common in melanomas compared to BRAF mutations, the dysfunction of the p53 pathway can also contribute to melanoma development and aggressiveness.

To explore potential interactions between oncogenic BRAF and p53, the study examined two melanoma cell lines with differing p53 status: SK-MEL-28, which harbors a mutated, oncogenic form of p53, and A375, which retains wild-type p53. Immunoprecipitation experiments indicated that BRAF preferentially interacts with oncogenic p53. Notably, ITF2357 not only reduced BRAF levels but also decreased oncogenic p53 levels in SK-MEL-28 cells. In A375 cells, ITF2357 targeted BRAF without affecting wild-type p53, which instead increased, potentially promoting apoptosis.

Silencing experiments further confirmed that the cellular response to ITF2357 in BRAF-mutated melanoma cells depends on p53 status. These findings provide a mechanistic rationale for targeted therapy in melanoma, highlighting the importance of considering p53 status when designing treatment strategies. The study underscores the potential of ITF2357 as a therapeutic agent in BRAF-mutated melanomas, particularly in cases where p53 function is compromised.