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

Oncogenic BRAF mutations have been widely described in melanomas and promote tumour progression and chemoresistance. We previously provided evidence that the HDAC inhibitor ITF2357 (Givinostat) targets oncogenic BRAF in SK-MEL-28 and A375 melanoma cells. Here, we show that oncogenic BRAF localises t...

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Bibliographic Details
Published in:International journal of molecular sciences 2023-05, Vol.24 (11), p.9148
Main Authors: Celesia, Adriana, Franzò, Marzia, Di Liberto, Diana, Lauricella, Marianna, Carlisi, Daniela, D'Anneo, Antonella, Notaro, Antonietta, Allegra, Mario, Giuliano, Michela, Emanuele, Sonia
Format: Article
Language:English
Subjects:
Analysis
Apoptosis
Autophagy
BRAF
Cancer therapies
Cell cycle
Chemoresistance
Cyclin-dependent kinases
Epigenetics
Gene mutations
Genetic aspects
HDAC inhibitor
Histone deacetylase
Immunoprecipitation
Inhibitors
ITF2357
Kinases
Localization
Medical prognosis
Melanoma
Mutation
p53
p53 Protein
Tumor proteins
Tumor suppressor genes
Tumors
Vemurafenib
Vorinostat
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Summary:Oncogenic BRAF mutations have been widely described in melanomas and promote tumour progression and chemoresistance. We previously provided evidence that the HDAC inhibitor ITF2357 (Givinostat) targets oncogenic BRAF in SK-MEL-28 and A375 melanoma cells. Here, we show that oncogenic BRAF localises to the nucleus of these cells, and the compound decreases BRAF levels in both the nuclear and cytosolic compartments. Although mutations in the tumour suppressor gene are not equally frequent in melanomas compared to BRAF, the functional impairment of the p53 pathway may also contribute to melanoma development and aggressiveness. To understand whether oncogenic BRAF and p53 may cooperate, a possible interplay was considered in the two cell lines displaying a different p53 status, being p53 mutated into an oncogenic form in SK-MEL-28 and wild-type in A375 cells. Immunoprecipitation revealed that BRAF seems to preferentially interact with oncogenic p53. Interestingly, ITF2357 not only reduced BRAF levels but also oncogenic p53 levels in SK-MEL-28 cells. ITF2357 also targeted BRAF in A375 cells but not wild-type p53, which increased, most likely favouring apoptosis. Silencing experiments confirmed that the response to ITF2357 in BRAF-mutated cells depends on p53 status, thus providing a rationale for melanoma-targeted therapy.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms24119148