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

Klieser, E.; Urbas, Romana; Stättner, Stefan; Primavesi, Florian; Jäger, Tarkan; Dinnewitzer, Adam; Mayr, Christian; Kiesslich, Tobias; Holzmann, Klaus; Fazio, Pietro Di; Neureiter, Daniel; Swierczynski, Stefan

doi:10.1016/j.humpath.2017.02.009

Cited by 54 publications

(39 citation statements)

References 28 publications

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“…Turning to HDAC5, high expression has been correlated with poorer prognosis in patients with BC or pancreatic neuroendocrine tumors and has been attributed to oncogenic effects [27,28]. Specifically, HDAC5 overexpression has been correlated with triple negative BC tumors [14,29].…”

Section: Discussionmentioning

confidence: 99%

“…A total of 107 patients were included, 60 were young women under 35 years (BCVY) and 47 samples from women over 45 years (BCO). The median age at breast cancer diagnosis in the young patient's group was 32 years (range, [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35], and in the old patient's group was 69 years (range, 53-94). Hereditary cases with BRCA1 and BRCA2 mutations were excluded from the study.…”

Section: Clinical-pathologic Characteristics Of Patientsmentioning

confidence: 99%

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HDAC5 Inhibitors as a Potential Treatment in Breast Cancer Affecting Very Young Women

Oltra

Cejalvo

Tormo

et al. 2020

Cancers

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Background: Breast cancer in very young women (BCVY) defined as <35 years old, presents with different molecular biology than in older patients. High HDAC5 expression has been associated with poor prognosis in breast cancer (BC) tissue. We aimed to analyze HDAC5 expression in BCVY and older patients and their correlation with clinical features, also studying the potential of HDAC5 inhibition in BC cell lines. Methods: HDAC5 expression in 60 BCVY and 47 older cases were analyzed by qRT-PCR and correlated with clinical data. The effect of the HDAC5 inhibitor, LMK-235, was analyzed in BC cell lines from older and young patients. We performed time and dose dependence viability, migration, proliferation, and apoptosis assays. Results: Our results correlate higher HDAC5 expression with worse prognosis in BCVY. However, we observed no differences between HDAC5 expression and pathological features. Our results showed greatly reduced progression in BCVY cell lines and also in all triple negative subtypes when cell lines were treated with LMK-235. Conclusions: In BCVY, we found higher expression of HDAC5. Overexpression of HDAC5 in BCVY correlates with lower survival rates. LMK-235 could be a potential treatment in BCVY.

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Section: Discussionmentioning

confidence: 99%

Section: Clinical-pathologic Characteristics Of Patientsmentioning

confidence: 99%

HDAC5 Inhibitors as a Potential Treatment in Breast Cancer Affecting Very Young Women

Oltra

Cejalvo

Tormo

et al. 2020

Cancers

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“…Hereby, we not only provide first data about a general involvement of these miRNAs in development and progression of pNETs, but also connect these miRNAs to HDAC expression and thus to epigenetic (de-)regulation. This is especially interesting since in a previous study investigating HDAC-deregulation in pNETs, we found specific HDAC family members to be linked with tumor grading, patient survival, and proliferation markers [ 22 ]. The expression levels of the set of miRNAs within our cohort of pNET samples followed a descending order with miRNA145-5p being expressed the highest and miRNA449a, the lowest (expression levels in descending order: 145-5p, 34a-5p, 132-3p, 183-5p, 449a).…”

Section: Discussionmentioning

confidence: 99%

“…Afterwards an immunoreactivity score (range 0–300) was calculated by multiplying the scores for intensity (0–3) and the stained cells (extensity, 0–100%) as previously published [ 53 ]. In addition, absolute quantitative scoring data of each HDAC, the relative data of low and high HDAC expressions levels were estimated according to the expression’s means as HDAC-specific cut-off-values, as previously published [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

HDAC-Linked “Proliferative” miRNA Expression Pattern in Pancreatic Neuroendocrine Tumors

Klieser

Urbas

Swierczynski

et al. 2018

IJMS

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Epigenetic factors are essentially involved in carcinogenesis, tumor promotion, and chemoresistance. Two epigenetic key players are miRNAs and histone deacetylases (HDACs). As previously shown by own theoretical databank analysis, the crosstalk between miRNAs and HDACs is relevant in different human chronic diseases and cancerogenic pathways. We aimed to investigate a potential connection between the expression of a well-defined subset of “proliferation-associated” miRNAs and the expression of HDACs as well as clinical parameters in pancreatic neuroendocrine tumors (pNETs). Materials and Methods: Expression levels of miRNA132-3p, miRNA145-5p, miRNA183-5p, miRNA34a-5p, and miRNA449a in 57 pNETs resected between 1997 and 2015 were measured and linked to the immunohistochemical expression pattern of members of the four HDAC classes on human tissue microarrays. All pNET cases were clinically and pathologically characterized according to published guidelines. Correlation analysis revealed a significant association between expression of specific miRNAs and two members of the HDAC family (HDAC3 and HDAC4). Additionally, a linkage between miRNA expression and clinico-pathological parameters like grading, TNM-staging, and hormone activity was found. Moreover, overall and disease-free survival is statistically correlated with the expression of the investigated miRNAs. Overall, we demonstrated that specific miRNAs could be linked to HDAC expression in pNETs. Especially miRNA449a (associated with HDAC3/4) seems to play an important role in pNET proliferation and could be a potential prognostic factor for poor survival. These first data could help, to improve our knowledge of the complex interactions of the epigenetic drivers in pNETs for further therapeutic approaches.

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“… Mammalian silent information regulator 1 (SIRT1) is reported to play a role in cancers of the secretory organs, including thyroid, pancreatic endocrine, and ovarian tumors [ 1 , 2 , 3 , 4 ]. A recent meta-analysis conducted on 37 selected studies of human cancers analyzed the correlations of overall survival (OS), disease-free survival (DFS) and relapse-free survival (RFS) with SIRT1 expression [ 5 ].…”

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confidence: 99%

SIRT1 in Secretory Organ Cancer

Frazzi

2018

Front. Endocrinol.

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Mammalian silent information regulator 1 (SIRT1) is reported to play a role in cancers of the secretory organs, including thyroid, pancreatic endocrine, and ovarian tumors [1, 2, 3, 4]. A recent meta-analysis conducted on 37 selected studies of human cancers analyzed the correlations of overall survival (OS), disease-free survival (DFS) and relapse-free survival (RFS) with SIRT1 expression [5]. This study reported that SIRT1 overexpression was associated with a worse OS in liver and lung cancers, while it was not correlated with OS in breast cancer, colorectal cancer, or gastric carcinoma. Collectively, the meta-analysis revealed that an unfavorable OS was associated with SIRT1 expression for solid malignancies. Given the growing importance of this class of lysine/histone deacetylases in human endocrine malignancies, a rational and focused literature assessment is desirable in light of future clinical translations.

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

Cited by 54 publications

References 28 publications

HDAC5 Inhibitors as a Potential Treatment in Breast Cancer Affecting Very Young Women

HDAC5 Inhibitors as a Potential Treatment in Breast Cancer Affecting Very Young Women

HDAC-Linked “Proliferative” miRNA Expression Pattern in Pancreatic Neuroendocrine Tumors

SIRT1 in Secretory Organ Cancer

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