title: Expression of the class 1 histone deacetylases HDAC8 and 3 are associated with improved survival of patients with metastatic melanoma.
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.
authors.affiliation: 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: Wilmott
authors.affiliation: 1] Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia [2] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Colebatch
authors.affiliation: 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Hojabr
authors.initials: H
authors.lastname: Kakavand
authors.affiliation: Melanoma Institute Australia, Sydney, New South Wales, Australia.
authors.forename: Ping
authors.initials: P
authors.lastname: Shang
authors.affiliation: 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia [3] Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia.
authors.forename: Matteo S
authors.initials: MS
authors.lastname: Carlino
authors.affiliation: 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Departments of Melanoma and Surgical Oncology, Camperdown, New South Wales, Australia [3] Mater Hospital, North Sydney, Sydney, New South Wales, Australia [4] Discipline of Surgery, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.affiliation: 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Departments of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia [3] Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia [3] Kolling Institute, Royal North Shore Hospital, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Hersey
mesh_terms: D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D016328:NF-kappa B; D048493:Proto-Oncogene Proteins B-raf; D012097:Repressor Proteins; D000099186:Histone Deacetylase 3; C409470:HDAC8 protein, human
references.citation: Cancer. 2012 Aug 15;118(16):4014-23
references.pmid: 22180178
references.citation: FASEB J. 2012 Jun;26(6):2437-45
references.pmid: 22389438
references.citation: Nucleic Acids Res. 2013 Jan 7;41(1):90-109
references.pmid: 23087373
references.citation: Cancer Res. 2005 Mar 15;65(6):2260-8
references.pmid: 15781639
references.citation: Nat Rev Cancer. 2006 Jan;6(1):38-51
references.pmid: 16397526
references.citation: Nature. 2002 Jun 27;417(6892):949-54
references.pmid: 12068308
references.citation: Pigment Cell Melanoma Res. 2014 Nov;27(6):1126-37
references.pmid: 24924589
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11160-5
references.pmid: 16847267
references.citation: Adv Pharmacol. 2012;65:27-43
references.pmid: 22959022
references.citation: J Invest Dermatol. 2013 Feb;133(2):509-17
references.pmid: 22931913
references.citation: Nat Genet. 2005 Apr;37(4):391-400
references.pmid: 15765097
references.citation: Oncogene. 2010 Nov 4;29(44):5957-68
references.pmid: 20697349
references.citation: Clin Cancer Res. 2009 Jan 1;15(1):91-9
references.pmid: 19118036
references.citation: Expert Rev Anticancer Ther. 2010 Jun;10(6):935-54
references.pmid: 20553216
references.citation: Am J Pathol. 2004 Aug;165(2):553-64
references.pmid: 15277229
references.citation: Cancer. 2012 Sep 15;118(18):4519-29
references.pmid: 22736239
references.citation: Mol Cancer Ther. 2011 Sep;10(9):1591-9
references.pmid: 21697394
references.citation: Oncogene. 2007 Mar 22;26(13):1954-8
references.pmid: 17001349
references.citation: Apoptosis. 2006 Dec;11(12 ):2251-65
references.pmid: 17051334
references.citation: J Biol Chem. 2000 May 19;275(20):15254-64
references.pmid: 10748112
references.citation: Br J Cancer. 2014 Jul 15;111(2):292-9
references.pmid: 24918823
references.citation: BMC Cancer. 2009 Nov 13;9:395
references.pmid: 19912635
references.citation: Cancer Res. 2008 May 15;68(10):3624-9
references.pmid: 18483244
references.citation: Cell Death Dis. 2013 Jun 06;4:e655
references.pmid: 23744355
references.citation: J Biol Chem. 2002 Mar 8;277(10):7920-8
references.pmid: 11773061
references.citation: FASEB J. 2005 Jun;19(8):966-8
references.pmid: 15772115
references.citation: Cancer Res. 2002 Dec 15;62(24):7335-42
references.pmid: 12499277
references.citation: Cell Death Differ. 2006 Dec;13(12):2033-41
references.pmid: 16628233
references.citation: Mol Cell Biol. 2004 Jan;24(2):765-73
references.pmid: 14701748
references.citation: Nature. 2013 Dec 5;504(7478):138-42
references.pmid: 24185007