PLX114990

GSE127564: Overexpression of HDAC8 establishes a unique gene signature in BRAF-mutant melanoma cells

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Systems level analyses using mass spectrometry-based phosphoproteomics and RNA-Seq implicated HDAC8 in the regulation of MAPK and AP-1 signaling pathways. Introduction of HDAC8 into drug-nave melanoma cells conveyed resistance both in vitro and in in vivo xenograft models. HDAC8-mediated BRAF inhibitor resistance was mediated via receptor tyrosine kinase (RTK) activation leading to Ras/CRAF/MEK/ERK signaling. Although HDACs primarily function at the histone level, they also regulate signaling through the modulation of non-histone substrates. In line with this, HDAC8 introduction decreased the acetylation of c-Jun, increasing its transcriptional activity and enriching for an AP-1 gene signature. Mutation of the putative c-Jun acetylation site at lysine residue 273 reduced the transcriptional activation of c-Jun in melanoma cells and conveyed resistance to BRAF inhibition through increased RTK expression and enhanced MAPK pathway activity. SOURCE: Keiran Smalley (Keiran.Smalley@moffitt.org) - Moffitt Cancer Center