Retinoic acid receptor beta2 is epigenetically silenced either by DNA methylation or repressive histone modifications at the promoter in cervical cancer cells.
To elucidate the silencing mechanism of retinoic acid receptor beta2 (RAR beta2) in cervical carcinogenesis, we investigated RAR beta2 expression and the status of both DNA methylation and histone modifications at the promoter in cervical cancer cell lines. RAR beta2 was frequently repressed in cancer cell lines and in primary cancers of the cervix. Although the majority of RAR beta2-negative cancers had methylated promoter, RAR beta2 was repressed with hypomethylated promoter in a substantial fraction of the cancers. The RAR beta2-negative cells with hypomethylated promoters showed a repressive histone modification pattern at the promoter. RAR beta2 was reactivated by a histone deacetylase inhibitor, accompanied by formation of active histone modifications. The repressive modification was also observed in cells repressed with hypermethylated promoter, but RAR beta2 was reactivated only by DNA demethylating agent and not by histone deacetylase inhibitor. Our results suggest that RAR beta2 is silenced by either of the two key epigenetic pathways, DNA methylation or repressive histone modifications, depending on the individual cancer cells.
Zhang
Zhongming
Z
Division of Molecular Biology and Genetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga 849-8501, Japan.
Joh
Keiichiro
K
Yatsuki
Hitomi
H
Zhao
Wei
W
Soejima
Hidenobu
H
Higashimoto
Ken
K
Noguchi
Mitsuyo
M
Yokoyama
Masatoshi
M
Iwasaka
Tsuyoshi
T
Mukai
Tsunehiro
T
D001483:Base Sequence; D045744:Cell Line, Tumor; D019175:DNA Methylation; D017931:DNA Primers; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D006657:Histones / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology
D017931:DNA Primers; D006657:Histones; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta