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Cancer Res. 2019 Jun 1;79(11):2947-2961. doi: 10.1158/0008-5472.CAN-19-0040. Epub 2019 Apr 15.

HDAC8 Regulates a Stress Response Pathway in Melanoma to Mediate Escape from BRAF Inhibitor Therapy.

Author information

1
The Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
2
The Department of Molecular Oncology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
3
Department of Bioinformatics and Biostatistics, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
4
The Department of Cutaneous Oncology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
5
Department of Translational Skin Cancer Research, German Cancer Consortium (DKTK), University Hospital Essen, Essen, Germany.
6
George Washington University, Washington, D.C.
7
The University of Florida Health Cancer Center, Gainesville, Florida.
8
The Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, Florida. keiran.smalley@moffitt.org.

Abstract

Melanoma cells have the ability to switch to a dedifferentiated, invasive phenotype in response to multiple stimuli. Here, we show that exposure of melanomas to multiple stresses including BRAF-MEK inhibitor therapy, hypoxia, and UV irradiation leads to an increase in histone deacetylase 8 (HDAC8) activity and the adoption of a drug-resistant phenotype. Mass spectrometry-based phosphoproteomics implicated HDAC8 in the regulation of MAPK and AP-1 signaling. Introduction of HDAC8 into drug-naïve melanoma cells conveyed resistance both in vitro and in vivo. HDAC8-mediated BRAF inhibitor resistance was mediated via receptor tyrosine kinase activation, leading to MAPK signaling. Although HDACs function at the histone level, they also regulate nonhistone substrates, and introduction of HDAC8 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 273 increased transcriptional activation of c-Jun in melanoma cells and conveyed resistance to BRAF inhibition. In vivo xenograft studies confirmed the key role of HDAC8 in therapeutic adaptation, with both nonselective and HDAC8-specific inhibitors enhancing the durability of BRAF inhibitor therapy. Our studies demonstrate that HDAC8-specific inhibitors limit the adaptation of melanoma cells to multiple stresses including BRAF-MEK inhibition. SIGNIFICANCE: This study provides evidence that HDAC8 drives transcriptional plasticity in melanoma cells in response to a range of stresses through direct deacetylation of c-Jun.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/11/2947/F1.large.jpg.

PMID:
30987999
PMCID:
PMC6548652
[Available on 2020-06-01]
DOI:
10.1158/0008-5472.CAN-19-0040

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