MUC1 expression is regulated by DNA methylation and histone H3 lysine 9 modification in cancer cells.
MUC1 is a transmembrane mucin that is highly expressed in various cancers and correlates with malignant potential. Important cancer-related genes such as p16 and E-cadherin are controlled epigenetically; however, MUC1 has been overlooked in epigenetics. Herein, we provide the first report that MUC1 gene expression is regulated by DNA methylation and histone H3 lysine 9 (H3-K9) modification of the MUC1 promoter. The recently developed MassARRAY assay was performed to investigate the DNA methylation status of 184 CpG sites from -2,753 to +263. Near the transcriptional start site, the DNA methylation level of MUC1-negative cancer cell lines (e.g., MDA-MB-453) was high, whereas that of MUC1-positive cell lines (e.g., MCF-7) was low. Histone H3-K9 modification status was also closely related to MUC1 gene expression. Furthermore, MUC1 mRNA expression in MUC1-negative cells was restored by treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine. Our results indicate that DNA methylation and histone H3-K9 modification in the 5' flanking region play a critical role in MUC1 gene expression, and this study defines MUC1 as a new member of the class of epigenetically controlled genes. An understanding of the epigenetic changes of MUC1 may be of importance for diagnosis of carcinogenic risk and prediction of outcome for cancer patients.
Yamada
Norishige
N
Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan.
Nishida
Yukari
Y
Tsutsumida
Hideaki
H
Hamada
Tomofumi
T
Goto
Masamichi
M
Higashi
Michiyo
M
Nomoto
Mitsuharu
M
Yonezawa
Suguru
S
D000230:Adenocarcinoma; D001483:Base Sequence; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D019175:DNA Methylation; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000235:genetics*; D010190:Pancreatic Neoplasms; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D004273:DNA, Neoplasm; D006657:Histones; C060192:MUC1 protein, human; D018396:Mucin-1; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D008239:Lysine