High class I HDAC activity and expression are associated with RelA/p65 activation in pancreatic cancer in vitro and in vivo.
BACKGROUND
The strong association between aberrant HDAC activity and the occurrence of cancer has led to the development of a variety of HDAC inhibitors (HDIs), which emerge as promising new targeted anticancer therapeutics.


METHODS
Due to the pivotal role of RelA/p65 in the tumorigenesis of pancreatic neoplasia we examined the expression of class I HDACs 1, 2 and 3 in a large cohort of human pancreatic carcinomas and correlated our findings with RelA/p65 expression status. Furthermore, we investigated the impact of the HDIs SAHA and VPA on RelA/p65 activity in pancreatic cancer cell culture models.


RESULTS
Class I HDACs were strongly expressed in a subset of pancreatic adenocarcinomas and high expression was significantly correlated with increased nuclear translocation of RelA/p65 (p = 0.024). The link of HDAC activity and RelA/p65 in this tumor entity was confirmed in vitro, where RelA/p65 nuclear translocation as well as RelA/p65 DNA binding activity could be markedly diminished by HDI treatment.


CONCLUSIONS
The RelA/p65 inhibitory effects of SAHA and VPA in vitro and the close relationship of class I HDACs and RelA/p65 in vivo suggest that treatment with HDIs could serve as a promising approach to suppress NF-kappaB activity which in turn may lead to enhanced apoptosis and chemosensitization of pancreatic cancers.
Lehmann
Annika
A
Institute of Pathology, Charité University Hospital, Berlin, Germany. annika.lehmann@charite.de
Denkert
Carsten
C
Budczies
Jan
J
Buckendahl
Ann-Christin
AC
Darb-Esfahani
Silvia
S
Noske
Aurelia
A
Müller
Berit Maria
BM
Bahra
Marcus
M
Neuhaus
Peter
P
Dietel
Manfred
M
Kristiansen
Glen
G
Weichert
Wilko
W
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D000099186:Histone Deacetylase 3
D004791:Enzyme Inhibitors; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D051996:Transcription Factor RelA; D000099186:Histone Deacetylase 3; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human