Monoamine oxidase A expression is suppressed in human cholangiocarcinoma via coordinated epigenetic and IL-6-driven events.
The secretion of dopamine and serotonin is increased in cholangiocarcinoma, which has growth-promoting effects. Monoamine oxidase A (MAOA), the degradation enzyme of serotonin and dopamine, is suppressed in cholangiocarcinoma via an unknown mechanism. The aims of this study were to (i) correlate MAOA immunoreactivity with pathophysiological parameters of cholangiocarcinoma, (ii) determine the mechanism by which MAOA expression is suppressed and (iii) evaluate the consequences of restored MAOA expression in cholangiocarcinoma. MAOA expression was assessed in cholangiocarcinoma and nonmalignant controls. The control of MAOA expression by promoter hypermethylation was evaluated and the contribution of interleukin-6 (IL-6) signaling to the suppression of MAOA expression was determined. The effects of MAOA overexpression on cholangiocarcinoma growth and invasion were also assessed. MAOA expression is correlated with differentiation, invasion and survival in cholangiocarcinoma. The MAOA promoter was hypermethylated immediately upstream of the start codon in cholangiocarcinoma samples and cell lines but not in nonmalignant counterparts. IL-6 signaling also decreased MAOA expression via a mechanism independent of hypermethylation, involving the regulation of the balance between SP-1 transcriptional activity and its inhibitor, R1 repressor. Inhibition of both IL-6 signaling and DNA methylation restored MAOA levels to those observed in cholangiocytes. Forced MAOA overexpression inhibited cholangiocarcinoma growth and invasion. MAOA expression is suppressed by the coordinated control of promoter hypermethylation and IL-6 signaling. MAOA may be a useful prognostic marker in the management of cholangiocarcinoma, and therapies designed to increase MAOA expression might prove beneficial in the treatment of cholangiocarcinoma.
Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Scott and White Hospital, Central Texas Veterans Health Care System, Temple, TX 76504, USA.
Li
L
Huang
Gabriel
G
Frampton
Arundhati
A
Rao
Kun-song
KS
Zhang
Wei
W
Chen
Jia-ming
JM
Lai
Xiao-yu
XY
Yin
Kimberly
K
Walker
Brianne
B
Culbreath
Dinorah
D
Leyva-Illades
Matthew
M
Quinn
Matthew
M
McMillin
Michelle
M
Bradley
Li-Jian
LJ
Liang
Sharon
S
DeMorrow
D000818:Animals; D001650:Bile Duct Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D001653:Bile Ducts, Intrahepatic / Q000201:enzymology*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D018281:Cholangiocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D015529:Choledochal Cyst / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation / Q000235:genetics; D004298:Dopamine / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism
C513450:CDCA7L protein, human; D015850:Interleukin-6; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; D012701:Serotonin; D008995:Monoamine Oxidase; D004298:Dopamine