TY - JOUR
T1 - Epigenetic inactivation of CHFR in human tumors
AU - Toyota, Minoru
AU - Sasaki, Yasushi
AU - Satoh, Ayumi
AU - Ogi, Kazuhiro
AU - Kikuchi, Takefumi
AU - Suzuki, Hiromu
AU - Mita, Hiroaki
AU - Tanaka, Nobuyuki
AU - Itoh, Fumio
AU - Issa, Jean Pierre J.
AU - Jair, Kam Wing
AU - Schuebel, Kornel E.
AU - Imai, Kohzoh
AU - Tokino, Takashi
PY - 2003/6/24
Y1 - 2003/6/24
N2 - Cell-cycle checkpoints controlling the orderly progression through mitosis are frequently disrupted in human cancers. One such checkpoint, entry into metaphase, is regulated by the CHFR gene encoding a protein possessing forkhead-associated and RING finger domains as well as ubiquitin-ligase activity. Although defects in this checkpoint have been described, the molecular basis and prevalence of CHFR inactivation in human tumors are still not fully understood. To address this question, we analyzed the pattern of CHFR expression in a number of human cancer cell lines and primary tumors. We found CpG methylation-dependent silencing of CHFR expression in 45% of cancer cell lines, 40% of primary colorectal cancers, 53% of colorectal adenomas, and 30% of primary head and neck cancers. Expression of CHFR was precisely correlated with both CpG methylation and deacetylation of histones H3 and H4 in the CpG-rich regulatory region. Moreover, CpG methylation and thus silencing of CHFR depended on the activities of two DNA methyltransferases, DNMT1 and DNMT3b, as their genetic inactivation restored CHFR expression. Finally, cells with CHFR methylation had an intrinsically high mitotic index when treated with microtubule inhibitor. This means that cells in which CHFR was epigenetically inactivated constitute loss-of-function alleles for mitotic checkpoint control. Taken together, these findings shed light on a pathway by which mitotic checkpoint is bypassed in cancer cells and suggest that inactivation of checkpoint genes is much more widespread than previously suspected.
AB - Cell-cycle checkpoints controlling the orderly progression through mitosis are frequently disrupted in human cancers. One such checkpoint, entry into metaphase, is regulated by the CHFR gene encoding a protein possessing forkhead-associated and RING finger domains as well as ubiquitin-ligase activity. Although defects in this checkpoint have been described, the molecular basis and prevalence of CHFR inactivation in human tumors are still not fully understood. To address this question, we analyzed the pattern of CHFR expression in a number of human cancer cell lines and primary tumors. We found CpG methylation-dependent silencing of CHFR expression in 45% of cancer cell lines, 40% of primary colorectal cancers, 53% of colorectal adenomas, and 30% of primary head and neck cancers. Expression of CHFR was precisely correlated with both CpG methylation and deacetylation of histones H3 and H4 in the CpG-rich regulatory region. Moreover, CpG methylation and thus silencing of CHFR depended on the activities of two DNA methyltransferases, DNMT1 and DNMT3b, as their genetic inactivation restored CHFR expression. Finally, cells with CHFR methylation had an intrinsically high mitotic index when treated with microtubule inhibitor. This means that cells in which CHFR was epigenetically inactivated constitute loss-of-function alleles for mitotic checkpoint control. Taken together, these findings shed light on a pathway by which mitotic checkpoint is bypassed in cancer cells and suggest that inactivation of checkpoint genes is much more widespread than previously suspected.
KW - DNA methylation
KW - DNA methyltransferase
KW - Histone deacetylation
KW - Mitotic checkpoint
UR - http://www.scopus.com/inward/record.url?scp=0037934421&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037934421&partnerID=8YFLogxK
U2 - 10.1073/pnas.1337066100
DO - 10.1073/pnas.1337066100
M3 - Article
C2 - 12810945
AN - SCOPUS:0037934421
SN - 0027-8424
VL - 100
SP - 7818
EP - 7823
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 13
ER -