Epigenetic inactivation of class II transactivator (CIITA) is associated with the absence of interferon-gamma-induced HLA-DR expression in colorectal and gastric cancer cells.
Tightly regulated at the level of transcription, expression of MHC class II molecules varies significantly among gastrointestinal cancers. High levels of MHC class II expression are often associated with a better prognosis, which is indicative of the involvement of CD4+ lymphocytes in tumor suppression, but the molecular mechanism by which MHC class II expression is regulated remains unclear. In the present study, we investigated the expression of one inducible MHC class II molecule, HLA-DR, and its coactivators in a panel of colorectal and gastric cancer cell lines. Interferon-gamma induced expression of HLA-DR in 14 of 20 cell lines tested; the remaining six cell lines did not express HLA-DR. Analysis of the expression of transcription factors and coactivators associated with HLA-DR revealed that the loss of CIITA expression was closely associated with the absence of HLA-DR induction. Moreover, DNA methylation of the 5' CpG island of CIITA-PIV was detected in all cancer cells that lacked CIITA. The methylation and resultant silencing of CIITA-PIV depended on the activities of two DNA methyltransferases, DNMT1 and DNMT3B, and their genetic inactivation restored CIITA-PIV expression. It thus appears that CIITA methylation is a key mechanism that enables some gastrointestinal cancer cells to escape immune surveillance.
First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan.
Ayumi
A
Satoh
Minoru
M
Toyota
Hideyuki
H
Ikeda
Yoshikazu
Y
Morimoto
Kimishige
K
Akino
Hiroaki
H
Mita
Hiromu
H
Suzuki
Yasushi
Y
Sasaki
Takayuki
T
Kanaseki
Yukio
Y
Takamura
Hidenobu
H
Soejima
Takeshi
T
Urano
Kazuyoshi
K
Yanagihara
Takao
T
Endo
Yuji
Y
Hinoda
Masahiro
M
Fujita
Masao
M
Hosokawa
Noriyuki
N
Sato
Takashi
T
Tokino
Kohzoh
K
Imai
D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D015179:Colorectal Neoplasms / Q000378:metabolism*; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005434:Flow Cytometry; D020868:Gene Silencing; D006684:HLA-DR Antigens / Q000378:metabolism*; D006657:Histones / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism*; D008239:Lysine / Q000737:chemistry; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics*; D010957:Plasmids / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism*; D013447:Sulfites / Q000494:pharmacology; D015534:Trans-Activators / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D006684:HLA-DR Antigens; D006657:Histones; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D013447:Sulfites; D015534:Trans-Activators; D007371:Interferon-gamma; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D008239:Lysine