Histone-deacetylase inhibitors induce the cathelicidin LL-37 in gastrointestinal cells.
Histone-deacetylase (HDAC) -inhibitors enhance acetylation of core proteins and this is linked to formation of transcriptionally active chromatin in various cells. In this study, the effect of HDAC inhibitors (butyrate, trichostatin A (TSA)) on the expression of the cathelicidin LL-37 in colon, gastric and hepatocellular cells was investigated.


METHODS
LL-37 expression was assessed in colon, gastric and hepatocellular cancer cells after treatment with HDAC-inhibitors. In parallel, histone H4 and HMGN2, a non-histone protein, acetylation was evaluated. In addition, the intracellular signalling pathway MEK-ERK was explored.


RESULTS
In contrast to normal colon epithelial cells, gastrointestinal cancer cells lacked LL-37 expression. LL-37 was induced following treatment with HDAC-inhibitors in all investigated cell lines. This induction was time-dependent in butyrate-treated cells while TSA exerted a transient effect. Induction of LL-37 by butyrate was paralleled by acetylation of the histone H4 and the non-histone HMGN2. Again, TSA resulted in transient acetylation. Furthermore, inhibition of MEK-ERK blocked HDAC inhibitor-induced LL-37 expression in colonic and gastric cells.


CONCLUSIONS
We have previously shown that butyrate induces LL-37 in colon epithelial cells. In the present study, we demonstrate that cathelicidin expression is modulated by HDAC-inhibitors in various gastrointestinal cells including gastric and hepatocellular cells. This is paralleled by changes in the acetylation of distinct core proteins suggesting a common regulatory mechanism of cathelicidin LL-37 regulation in these cells.
Schauber
Jürgen
J
Department of Medicine, Division of Gastroenterology, University of Würzburg, Josef-Schneider Str. 2, 97080 Würzburg, Germany. schauber_j@klinik.uni-wuerzburg.de
Iffland
Konrad
K
Frisch
Susanne
S
Kudlich
Theodor
T
Schmausser
Bernd
B
Eck
Matthias
M
Menzel
Thomas
T
Gostner
Andrea
A
Lührs
Hardi
H
Scheppach
Wolfgang
W
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D002087:Butyrates / Q000494:pharmacology; D054804:Cathelicidins; D005770:Gastrointestinal Neoplasms / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010802:Phylogeny; D015398:Signal Transduction / Q000502:physiology
D023181:Antimicrobial Cationic Peptides; D002087:Butyrates; D054804:Cathelicidins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases