H3K4 dimethylation in hepatocellular carcinoma is rare compared with other hepatobiliary and gastrointestinal carcinomas and correlates with expression of the methylase Ash2 and the demethylase LSD1

Magerl, Christian; Ellinger, Jörg; Braunschweig, Till; Kremmer, Elisabeth; Koch, Lin Kristin; Höller, Tobias; Büttner, Reinhard; Lüscher, Bernhard; Gütgemann, Ines

doi:10.1016/j.humpath.2009.08.007

« Previous Next »Human Pathology
Volume 41, Issue 2 , Pages 181-189, February 2010

H3K4 dimethylation in hepatocellular carcinoma is rare compared with other hepatobiliary and gastrointestinal carcinomas and correlates with expression of the methylase Ash2 and the demethylase LSD1

Christian Magerl
- Department of Pathology, University of Bonn, Sigmund-Freud-Straβe 25, 53127 Bonn, Germany
Jörg Ellinger, MD
- Department of Urology, University of Bonn, Sigmund-Freud-Straβe 25, 53127 Bonn, Germany
Till Braunschweig, MD
- Department of Pathology, University of Aachen, Pauwelsstraβe 30, 52074 Aachen, Germany
Elisabeth Kremmer, MD
- GSF-Institute of Molecular Immunology, Marchioninistraβe 25, 81377 München, Germany
Lin Kristin Koch, MD
- Department of Pathology, University of Bonn, Sigmund-Freud-Straβe 25, 53127 Bonn, Germany
Tobias Höller
- Institute for Biometry, Informatics and Epidemiology, University of Bonn, Sigmund-Freud-Straβe 25, 53105 Bonn, Germany
Reinhard Büttner, MD
- Department of Pathology, University of Bonn, Sigmund-Freud-Straβe 25, 53127 Bonn, Germany
Bernhard Lüscher, PhD
- Department of Biochemistry and Molecular Biology, RWTH Aachen University, Pauwelsstraβe 30, 52057 Aachen, Germany
Ines Gütgemann, MD
- Department of Pathology, University of Bonn, Sigmund-Freud-Straβe 25, 53127 Bonn, Germany
- Corresponding author.

Received 3 January 2009; received in revised form 7 July 2009; accepted 4 August 2009. published online 09 November 2009.

Summary

Methylation of core histones regulates chromatin structure and gene expression. Recent studies have demonstrated that these methylation patterns have prognostic value for some tumors. Therefore, we investigated dimethylation of histone H3 at lysine 4 (H3K4diMe) and H3K4 methylating (Ash2 complex) and demethylating enzymes (LSD1) in carcinomas of the hepatic and gastrointestinal tract. High levels of H3K4diMe were rarely observed in 15.7% of hepatocellular carcinoma (8/51) unlike other carcinomas including, in ascending order, cholangiocellular carcinoma/adenocarcinoma of the extrahepatic biliary tract, gastric carcinoma, pancreatic ductal adenocarcinoma, and neuroendocrine carcinoma (P < .001). Ash2 was expressed in 84.4% of hepatocellular carcinomas (38/45) and correlated directly with H3K4diMe modification (correlation coefficient r = 0.53) and LSD1 expression (r = 0.35). In contrast to other carcinomas, 65.9% (29/44) of hepatocellular carcinomas analyzed showed no LSD1 expression (P < .001). Interestingly, hepatocellular carcinomas without LSD1 expression appeared to be frequently Ash2 and H3K4diMe weak or negative (P = .004). In summary, high H3K4diMe expression is rare in hepatocellular carcinoma compared with other carcinomas (negative predictive value 92.3%), which may aid in the differential diagnosis. Lack of H3K4diMe is possibly due to complex epigenetic regulation involving Ash2 and LSD1.

Keywords: Epigenetic regulation, Histone methylation and demethylation, H3K4, LSD1, Ash2