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| Home > Publications database > Proteogenomic Analysis of HDAC4 and HDAC5 in Uveal Melanoma. |
| Journal Article | DKFZ-2026-02354 |
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2026
BioMed Central
[London]
Abstract: Uveal melanoma (UM) is a rare but aggressive cancer arising from cells of the uveal tract that is highly resistant to therapy once it has metastasized. In drug screening experiments, we identified a high sensitivity of primary UM cell lines to the pan-histone deacetylase (HDAC) inhibitor panobinostat and addressed the question whether two class IIa HDACs, HDAC4 and HDAC5, could serve as potential therapeutic targets in UM. Selective pharmacological inhibition of HDAC4/5, as well as stable knockdown of HDAC4 or HDAC5, did not strongly affect cell viability, differentiation, apoptosis or necrosis, and did not sensitize cells to other HDAC or MEK inhibitors. Proteogenomics analysis revealed 73% concordance and only 7% discordance in the expression of transcripts and proteins. Concordance reached 92% for significant transcripts. Despite the lack of severe global gene and protein expression changes in HDAC4- or HDAC5-knockdown UM cell lines, the expression of individual cancer-related genes and signaling pathways was differently regulated following HDAC4 or HDAC5 knockdown. This was particularly evident in the NF-κB pathway, which showed decreased NF-κB p65 phosphorylation in UM cell lines with monosomy in chromosome 3 (M3) genotype and mutations in BRCA1-associated protein 1 (BAP1). In summary, our results suggest that HDAC4/5 inhibitors alone are insufficient for monotherapy in UM cells, but the identification of HDAC4/5-regulated genes involved in cancer progression provides a rationale for exploring combination strategies that include HDAC4/5 inhibition.
Keyword(s): Humans (MeSH) ; Histone Deacetylases: genetics (MeSH) ; Histone Deacetylases: metabolism (MeSH) ; Uveal Neoplasms: genetics (MeSH) ; Uveal Neoplasms: metabolism (MeSH) ; Uveal Neoplasms: pathology (MeSH) ; Uveal Melanoma (MeSH) ; Melanoma: genetics (MeSH) ; Melanoma: metabolism (MeSH) ; Melanoma: pathology (MeSH) ; Cell Line, Tumor (MeSH) ; Repressor Proteins: genetics (MeSH) ; Repressor Proteins: metabolism (MeSH) ; Repressor Proteins: antagonists & inhibitors (MeSH) ; Histone Deacetylase Inhibitors: pharmacology (MeSH) ; Gene Expression Regulation, Neoplastic: drug effects (MeSH) ; Proteogenomics: methods (MeSH) ; Signal Transduction: drug effects (MeSH) ; Gene Knockdown Techniques (MeSH) ; Tumor Suppressor Proteins: genetics (MeSH) ; Tumor Suppressor Proteins: metabolism (MeSH) ; Ubiquitin Thiolesterase: genetics (MeSH) ; Ubiquitin Thiolesterase: metabolism (MeSH) ; Panobinostat: pharmacology (MeSH) ; Apoptosis: drug effects (MeSH) ; NF-kappa B: metabolism (MeSH) ; Choroid Melanoma ; HDAC ; Histone Deacetylases ; Histone Deacetylases ; HDAC5 protein, human ; HDAC4 protein, human ; Repressor Proteins ; Histone Deacetylase Inhibitors ; Tumor Suppressor Proteins ; Ubiquitin Thiolesterase ; BAP1 protein, human ; Panobinostat ; NF-kappa B
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