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Expression of the class 1 histone deacetylases HDAC8 and 3 are associated with improved survival of patients with metastatic melanoma.
- Source :
-
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc [Mod Pathol] 2015 Jul; Vol. 28 (7), pp. 884-94. Date of Electronic Publication: 2015 Apr 03. - Publication Year :
- 2015
-
Abstract
- Prior studies have shown that combinations of histone deacetylase (HDAC) and BRAF inhibitors (BRAFi) have synergistic effects on BRAFi-resistant melanoma through enhanced apoptosis and inhibition of the cAMP-dependent drug resistance pathway. However, little is known about the expression of various HDACs and their associations with BRAF/NRAS mutation status, clinicopathologic characteristics, and patient outcome. The present study extensively profiled HDAC class 1 and their targets/regulators utilizing immunohistochemistry in human melanoma samples from patients with stage IV melanoma, known BRAF/NRAS mutational status, and detailed clinicopatholgical data. HDAC8 was increased in BRAF-mutated melanoma (P=0.016), however, no association between expression of other HDACs and NRAS/BRAF status was identified. There was also a correlation between HDAC1, HDAC8 expression, and phosphorylated NFκb p65 immunoreactivity (P<0.001). Increased cytoplasmic HDAC8 immunoreactivity was independently associated with an improved survival from both diagnosis of primary melanoma and from first detection of stage IV disease to melanoma death on multivariate analysis (HR 0.992, 95% CI 0.987-0.996; P<0.001 and HR 0.993, 95% CI 0.988-0.998; P=0.009, respectively). These results suggest not only that HDAC8 may be a prognostic biomarker in melanoma, but also provide important data regarding the regulation of HDACs in melanoma and a rational basis for targeting them therapeutically.
- Subjects :
- Cytoplasm metabolism
Female
Humans
Male
Melanoma mortality
Melanoma pathology
Mutation
NF-kappa B metabolism
Phosphorylation
Prognosis
Proto-Oncogene Proteins B-raf metabolism
Skin Neoplasms mortality
Skin Neoplasms pathology
Survival Rate
Histone Deacetylases metabolism
Melanoma metabolism
Repressor Proteins metabolism
Skin Neoplasms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1530-0285
- Volume :
- 28
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
- Publication Type :
- Academic Journal
- Accession number :
- 25836739
- Full Text :
- https://doi.org/10.1038/modpathol.2015.34