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.
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.
Magerl
Christian
C
Department of Pathology, University of Bonn, Sigmund-Freud-Strabetae 25, 53127 Bonn, Germany.
Ellinger
Jörg
J
Braunschweig
Till
T
Kremmer
Elisabeth
E
Koch
Lin Kristin
LK
Höller
Tobias
T
Büttner
Reinhard
R
Lüscher
Bernhard
B
Gütgemann
Ines
I
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism; D017734:Bile Ducts, Extrahepatic / Q000378:metabolism; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D016009:Chi-Square Distribution; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
C485622:ASH2L protein, human; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; D014157:Transcription Factors; D056466:Histone Demethylases; C495195:KDM1A protein, human; D008239:Lysine