title: Comprehensive immunohistochemical analysis of histone deacetylases in pancreatic neuroendocrine tumors: HDAC5 as a predictor of poor clinical outcome.
abstract: Epigenetic factors contribute to carcinogenesis, tumor promotion, and chemoresistance. Histone deacetylases (HDACs) are epigenetic regulators that primarily cause chromatin compaction, leading to inaccessibility of promoter regions and eventually gene silencing. Many cancer entities feature overexpression of HDACs. Currently, the role of HDACs in pancreatic neuroendocrine tumors (pNETs) is unclear. We analyzed the expression patterns of all HDAC classes (classes I, IIA, IIB, III, and IV) in 5 human tissue microarrays representing 57 pNETs resected between 1997 and 2013 and corresponding control tissue. All pNET cases were characterized clinically and pathologically according to recent staging guidelines. The investigated cases included 32 (56.1%) female and 25 (43.9%) male pNET patients (total n=57, 47.4% immunohistochemically endocrine positive). Immunohistochemical profiling revealed a significant up-regulation of all HDAC classes in pNET versus control, with different levels of intensity and extensity ranging from 1.5- to >7-fold up-regulation. In addition, expression of several HDACs (HDAC1, HDAC2, HDAC5, HDAC11, and Sirt1) was significantly increased in G3 tumors. Correlation analysis showed a significant association between the protein expression of HDAC classes I, III, and IV and rate of the pHH3/Ki-67-associated mitotic and proliferation index. Furthermore, especially HDAC5 proved as a negative predictor of disease-free and overall survival in pNET patients. Overall, we demonstrate that specific members of all 4 HDAC classes are heterogeneously expressed in pNET. Moreover, expression of HDACs was associated with tumor grading, proliferation markers, and patient survival, therefore representing interesting new targets in pNET treatment.
authors.affiliation: Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria. Electronic address: e.klieser@salk.at.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Klieser
authors.affiliation: Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria. Electronic address: r.urbas@salk.at.
authors.forename: Romana
authors.initials: R
authors.lastname: Urbas
authors.affiliation: Department of Visceral, Transplant and Thoracic Surgery, Medical University Innsbruck, 6020 Innsbruck, Austria. Electronic address: stefan.staettner@tirol-kliniken.at.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stättner
authors.affiliation: Department of Visceral, Transplant and Thoracic Surgery, Medical University Innsbruck, 6020 Innsbruck, Austria. Electronic address: florian.primavesi@tirol-kliniken.at.
authors.forename: Florian
authors.initials: F
authors.lastname: Primavesi
authors.affiliation: Department of Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria. Electronic address: ta.jaeger@salk.at.
authors.forename: Tarkan
authors.initials: T
authors.lastname: Jäger
authors.affiliation: Department of Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria. Electronic address: a.dinnewitzer@salk.at.
authors.forename: Adam
authors.initials: A
authors.lastname: Dinnewitzer
authors.affiliation: Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria; Laboratory for Tumour Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria. Electronic address: christian.mayr@pmu.ac.at.
authors.forename: Christian
authors.initials: C
authors.lastname: Mayr
authors.affiliation: Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria; Laboratory for Tumour Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria. Electronic address: t.kiesslich@salk.at.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kiesslich
authors.affiliation: Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna 1090, Austria. Electronic address: klaus.holzmann@meduniwien.ac.at.
authors.forename: Klaus
authors.initials: K
authors.lastname: Holzmann
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, 35043 Marburg, Germany. Electronic address: difazio@med.uni-marburg.de.
authors.forename: Pietro
authors.initials: P
authors.lastname: Di Fazio
authors.affiliation: Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria. Electronic address: d.neureiter@salk.at.
authors.forename: Daniel
authors.initials: D
authors.lastname: Neureiter
authors.affiliation: Department of Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria. Electronic address: stefan.swierczynski@gmail.com.
authors.forename: Stefan
authors.initials: S
authors.lastname: Swierczynski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D049109:Cell Proliferation; D018572:Disease-Free Survival; D005260:Female; D056284:Histone Deacetylase 1 / Q000032:analysis; D056464:Histone Deacetylase 2 / Q000032:analysis; D006655:Histone Deacetylases / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D008938:Mitosis; D060787:Neoplasm Grading; D018358:Neuroendocrine Tumors / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D011237:Predictive Value of Tests; D012307:Risk Factors; D056564:Sirtuin 1 / Q000032:analysis; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C447939:SIRT1 protein, human; D056564:Sirtuin 1; C110550:HDAC1 protein, human; C462506:HDAC11 protein, human; C533423:HDAC2 protein, human; C404500:HDAC5 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases
keywords: Disease-free survival; Expression analysis; HDAC; Overall survival; Pancreatic neuroendocrine tumor; Proliferation