Comprehensive immunohistochemical analysis of histone deacetylases in pancreatic neuroendocrine tumors: HDAC5 as a predictor of poor clinical outcome

Publication date: Available online 22 February 2017
Source:Human Pathology
Author(s): Eckhard Klieser, Romana Urbas, Stefan Stättner, Florian Primavesi, Tarkan Jäger, Adam Dinnewitzer, Christian Mayr, Tobias Kiesslich, Klaus Holzmann, Pietro Di Fazio, Daniel Neureiter, Stefan Swierczynski
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 over-expression of HDACs. Currently, the role of HDACs in pancreatic neuroendocrine tumors (pNETs) is unclear. We analyzed expression patterns of all HDAC classes (Class I, IIA, IIB, III & IV) in five human tissue microarrays (TMA) 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. Additionally, expression of several HDACs (HDAC-1, −2, −5, −11 and Sirt 1) 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 HDAC-5 proved as a negative predictor of disease-free and overall survival in pNET patients. Overall, we demonstrate that specific members of all four 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.



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