Human acyl-CoA:cholesterol acyltransferase 2 gene expression in intestinal Caco-2 cells and in hepatocellular carcinoma.
Humans express two ACAT (acyl-CoA:cholesterol acyltransferase) genes, ACAT1 and ACAT2. ACAT1 is ubiquitously expressed, whereas ACAT2 is primarily expressed in intestinal mucosa and plays an important role in intestinal cholesterol absorption. To investigate the molecular mechanism(s) responsible for the tissue-specific expression of ACAT2, we identified five cis-elements within the human ACAT2 promoter, four for the intestinal-specific transcription factor CDX2 (caudal type homeobox transcription factor 2), and one for the transcription factor HNF1alpha (hepatocyte nuclear factor 1alpha). Results of luciferase reporter and electrophoretic mobility shift assays show that CDX2 and HNF1alpha exert a synergistic effect, enhancing the ACAT2 promoter activity through binding to these cis-elements. In undifferentiated Caco-2 cells, the ACAT2 expression is increased when exogenous CDX2 and/or HNF1alpha are expressed by co-transfection. In differentiated Caco-2 cells, the ACAT2 expression significantly decreases when the endogenous CDX2 or HNF1alpha expression is suppressed by using RNAi (RNA interference) technology. The expression levels of CDX2, HNF1alpha, and ACAT2 are all greatly increased when the Caco-2 cells differentiate to become intestinal-like cells. These results provide a molecular mechanism for the tissue-specific expression of ACAT2 in intestine. In normal adult human liver, CDX2 expression is not detectable and the ACAT2 expression is very low. In the hepatoma cell line HepG2 the CDX2 expression is elevated, accounting for its elevated ACAT2 expression. A high percentage (seven of fourteen) of liver samples from patients affected with hepatocellular carcinoma exhibited elevated ACAT2 expression. Thus, the elevated ACAT2 expression may serve as a new biomarker for certain form(s) of hepatocellular carcinoma.
Song
Bao-Liang
BL
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Wang
Can-Hua
CH
Yao
Xiao-Min
XM
Yang
Li
L
Zhang
Wen-Jing
WJ
Wang
Zhen-Zhen
ZZ
Zhao
Xiao-Nan
XN
Yang
Jin-Bo
JB
Qi
Wei
W
Yang
Xin-Ying
XY
Inoue
Kenji
K
Lin
Zhi-Xin
ZX
Zhang
Hui-Zhan
HZ
Kodama
Tatsuhiko
T
Chang
Catherine C Y
CC
Liu
Yin-Kun
YK
Chang
Ta-Yuan
TY
Li
Bo-Liang
BL
D000328:Adult; D000071616:CDX2 Transcription Factor; D018938:Caco-2 Cells; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology*; D008297:Male; D009154:Mutation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000235:genetics*; D000097587:Sterol O-Acyltransferase 2
D000071616:CDX2 Transcription Factor; D051538:Hepatocyte Nuclear Factor 1-alpha; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C491270:CDX2 protein, human