Epigenetic inactivation of CHFR in human tumors

Minoru Toyota, Yasushi Sasaki, Ayumi Satoh, Kazuhiro Ogi, Takefumi Kikuchi, Hiromu Suzuki, Hiroaki Mita, Nobuyuki Tanaka, Fumio Itoh, Jean Pierre J. Issa, Kam Wing Jair, Kornel Schuebel, Kohzoh Imai, Takashi Tokino

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7818-7823
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number13
DOIs
StatePublished - Jun 24 2003

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Epigenomics
Methylation
M Phase Cell Cycle Checkpoints
Neoplasms
Histones
RING Finger Domains
Forkhead Transcription Factors
Mitotic Index
Nucleic Acid Regulatory Sequences
Methyltransferases
Gene Silencing
Metaphase
Ligases
Head and Neck Neoplasms
Ubiquitin
Cell Cycle Checkpoints
Tumor Cell Line
Mitosis
Microtubules
Adenoma

Keywords

  • DNA methylation
  • DNA methyltransferase
  • Histone deacetylation
  • Mitotic checkpoint

ASJC Scopus subject areas

  • General

Cite this

Toyota, M., Sasaki, Y., Satoh, A., Ogi, K., Kikuchi, T., Suzuki, H., ... Tokino, T. (2003). Epigenetic inactivation of CHFR in human tumors. Proceedings of the National Academy of Sciences of the United States of America, 100(13), 7818-7823. https://doi.org/10.1073/pnas.1337066100

Epigenetic inactivation of CHFR in human tumors. / Toyota, Minoru; Sasaki, Yasushi; Satoh, Ayumi; Ogi, Kazuhiro; Kikuchi, Takefumi; Suzuki, Hiromu; Mita, Hiroaki; Tanaka, Nobuyuki; Itoh, Fumio; Issa, Jean Pierre J.; Jair, Kam Wing; Schuebel, Kornel; Imai, Kohzoh; Tokino, Takashi.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 13, 24.06.2003, p. 7818-7823.

Research output: Contribution to journalArticle

Toyota, M, Sasaki, Y, Satoh, A, Ogi, K, Kikuchi, T, Suzuki, H, Mita, H, Tanaka, N, Itoh, F, Issa, JPJ, Jair, KW, Schuebel, K, Imai, K & Tokino, T 2003, 'Epigenetic inactivation of CHFR in human tumors', Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 13, pp. 7818-7823. https://doi.org/10.1073/pnas.1337066100
Toyota, Minoru ; Sasaki, Yasushi ; Satoh, Ayumi ; Ogi, Kazuhiro ; Kikuchi, Takefumi ; Suzuki, Hiromu ; Mita, Hiroaki ; Tanaka, Nobuyuki ; Itoh, Fumio ; Issa, Jean Pierre J. ; Jair, Kam Wing ; Schuebel, Kornel ; Imai, Kohzoh ; Tokino, Takashi. / Epigenetic inactivation of CHFR in human tumors. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 13. pp. 7818-7823.
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AU - Toyota, Minoru

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AU - Ogi, Kazuhiro

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AU - Suzuki, Hiromu

AU - Mita, Hiroaki

AU - Tanaka, Nobuyuki

AU - Itoh, Fumio

AU - Issa, Jean Pierre J.

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