HDAC8 regulates a stress response pathway in melanoma to mediate escape from BRAF inhibitor therapy
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Abstract
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.
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HDAC8 inhibitor plus BRAF inhibitor PLX4720 restores efficacy in inhibiting tumor growth and melanoma phenotype in vivo.
“Moreover, concomitant treatment with a HDAC8 inhibitor (Fig. 3) and a BRAF inhibitor (PLX4720) restores efficacy in inhibiting tumor growth and melanoma phenotype in vivo.(Emmons et al., 2019).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Emmons et al., 2019
HDAC8 supports a mechanism of therapy resistance in melanoma.
“In addition to the role of HDAC3 in melanoma described above, HDAC8 supports another mechanism of therapy resistance.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Emmons et al., 2019
HDAC8 deacetylates c-Jun to enhance its transcriptional activity.
“Mechanistically, HDAC8 deacetylates c-Jun to enhance its transcriptional activity.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Emmons et al., 2019
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- Authors
- Emmons, M. F., Faião-Flores, F., Sharma, R., Thapa, R., Messina, J. L., Becker, J. C., Schadendorf, D., Seto, E., Sondak, V. K., Koomen, J. M., Chen, Y. A., Lau, E. K., Wan, L., Licht, J. D., & Smalley, K. S. M.
- Affiliations
- Moffitt Cancer Center (US)
- 1The Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
- 5Department of Translational Skin Cancer Research, German Cancer Consortium (DKTK), University Hospital Essen, Essen, Germany.
- Essen University Hospital (DE)
- George Washington University (US)
- UF Health Cancer Center (US)
- Corresponding author
- Smalley, Keiran S.M.
- ORCID
- Venue
- Cancer Research
- Published
- 2019-06-01
- Volume
- 79
- Issue
- 11
- Pages
- 2947-2961
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC6548652
- OpenAlex
- W2939970176
- Cited by
- 73
- References
- 47
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 3 · 2023: 9 · 2022: 15 · 2021: 12 · 2020: 14 · 2019: 7
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- SPORE (P50 CA168536)
- NCI (R21 CA216756)
- Florida Department of Health (8BC03)
- Forma Therapeutics
- Proteomics and Metabolomics Core
- Biostatistics and Bioinformatics Core
- NCI-designated Comprehensive Cancer Center (P30-CA076292)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- HDAC8, melanoma, BRAF inhibitor resistance, MAPK signaling, AP-1 transcription factor, hypoxia, UV irradiation, histone deacetylase, drug resistance, transcriptional plasticity, HDAC8 inhibitors, receptor tyrosine kinase activation
- MeSH terms
- Panobinostat, Acetylation, Animals, Histone Deacetylases, Humans, Melanoma, Repressor Proteins, Skin Neoplasms, Stress, Physiological, Mice, Inbred NOD, Drug Resistance, Neoplasm, MAP Kinase Signaling System, Cell Line, Tumor, Protein Kinase Inhibitors, JNK Mitogen-Activated Protein Kinases, Proto-Oncogene Proteins B-raf, Histone Deacetylase Inhibitors
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