Histone deacetylase inhibitors in pancreatic cancer

Doctoral Dissertation uoadl:1306106 576 Read counter

Unit:
Τομέας Χειρουργικής
Library of the School of Health Sciences
Deposit date:
2015-07-03
Year:
2015
Author:
Δαμάσκος Χρήστος
Dissertation committee:
Καθηγητής Χειρουργικής ΕΚΠΑ Γρηγόριος Κουράκλης
Original Title:
Δράση των αναστολέων της ακετυλίωσης ιστονών στον καρκίνο του παγκρέατος
Languages:
Greek
Translated title:
Histone deacetylase inhibitors in pancreatic cancer
Summary:
Introduction: Acetylation and deacetylation of histones are important
mechanisms of epigenetic transcriptional regulation, which are regulated by
histone acetyltransferases (HAT) and histone deacetylases (HDAC), respectively.
These enzymes regulate the expression of genes controlling cell proliferation,
differentiation and apoptosis. Enhanced activity of HDAC results in suppression
of cell proliferation, migration and metastasis and induction of cell cycle
arrest and apoptosis. We tried to assess the expression of HDAC-1, -2, -4 and
-6 in pancreatic cancer.
Patients and methods: Formalin-fixed, paraffin-embedded tissue specimens were
obtained from 70 patients with pancreatic adenocarcinoma who underwent surgical
resection without previous treatment. We assessed the expression of HDAC-1, -2,
-4 and -6 by estimating the immunohistochemical staining for these proteins
using polyclonal and monoclonal IgG antibodies against them. The results were
associated with patients’ clinicopathological parameters and survival.
Results: The distribution of HDAC-1 and HDAC-2 was nuclear and of HDAC-4 and
HDAC-6 cytoplasmic. Expression of HDAC-1, -2, -4 and -6 was detected in 64.3%,
74.2%, 69.1% and 63.1% of malignant tissues, respectively, whereas no
expression was found in non-neoplastic tissues. High levels of HDAC-1, -2, -4
and -6 were detected in 40%, 50%, 48.6% and 44.3% of cases, respectively. High
HDAC-1 expression was associated with increased proliferation of malignant
cells, but also with longer survival. Increased HDAC-4 levels were related to
the absence of distant metastases. High HDAC-6 expression was associated with
earlier stages of disease and longer survival.
Conclusions: Elevated HDAC expression is associated with favorable
clinicopathological parameters and better prognosis. These findings implicate a
role of HDAC in the biological mechanisms of pancreatic cancer, rendering them
potential therapeutic targets for this malignant disease in the future. More
studies are needed towards this direction.
Keywords:
Pancreatic cancer, Acetylasation, Histone, Inhibitors, Targeted therapies
Index:
No
Number of index pages:
0
Contains images:
Yes
Number of references:
446
Number of pages:
240
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