Retinoblastoma pathway dysregulation causes DNA methyltransferase 1 overexpression in cancer via MAD2-mediated inhibition of the anaphase-promoting complex

Agoston T. Agoston, Pedram Argani, Angelo Michael Demarzo, Jessica L. Hicks, William G Nelson

Research output: Contribution to journalArticle

Abstract

We have examined the mechanism of normal DNA methyltransferase 1 (DNMT1) degradation as well as its mechanism of dysregulation in cancer. We have previously reported that DNMT1 protein levels were elevated and abnormally stabilized because of defective degradation through its N-terminal destruction domain. Here, we report that DNMT1 was abnormally stabilized in several cancer cell lines and that, in cells with normal DNMT1 destruction, depletion of CDC20 or FZR1 (two substrate recognition adaptor components of the anaphase-promoting complex) resulted in stabilization of DNMT1 that was partially dependent on the N-terminal destruction domain, thus implicating this cell cycle regulator in the destruction of DNMT1. MAD2, an inhibitor of CDC20, was shown to stabilize DNMT1 levels, and overexpression of MAD2, a consequence of retinoblastoma (RB) pathway dysregulation, was shown to correlate with impaired G, phase DNMT1 destruction and RB inactivation by hyperphosphorylation in several normal and cancer cell lines. Furthermore, in a series of 85 cases of human breast cancer, a moderately strong, but highly significant, correlation between MAD2 and DNMT1 immunohistochemical staining was observed, yielding a Spearman rank order correlation coefficient of 0.37 (P <0.001). This suggests that RB pathway inactivation, a common dysfunction in cancer cells, may be the underlying cause of DNMT1 dysregulation.

Original languageEnglish (US)
Pages (from-to)1585-1593
Number of pages9
JournalAmerican Journal of Pathology
Volume170
Issue number5
DOIs
StatePublished - May 2007

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Anaphase-Promoting Complex-Cyclosome
Retinoblastoma
Methyltransferases
DNA
Neoplasms
Protein Methyltransferases
Cell Line
Nonparametric Statistics
Cell Cycle

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

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title = "Retinoblastoma pathway dysregulation causes DNA methyltransferase 1 overexpression in cancer via MAD2-mediated inhibition of the anaphase-promoting complex",
abstract = "We have examined the mechanism of normal DNA methyltransferase 1 (DNMT1) degradation as well as its mechanism of dysregulation in cancer. We have previously reported that DNMT1 protein levels were elevated and abnormally stabilized because of defective degradation through its N-terminal destruction domain. Here, we report that DNMT1 was abnormally stabilized in several cancer cell lines and that, in cells with normal DNMT1 destruction, depletion of CDC20 or FZR1 (two substrate recognition adaptor components of the anaphase-promoting complex) resulted in stabilization of DNMT1 that was partially dependent on the N-terminal destruction domain, thus implicating this cell cycle regulator in the destruction of DNMT1. MAD2, an inhibitor of CDC20, was shown to stabilize DNMT1 levels, and overexpression of MAD2, a consequence of retinoblastoma (RB) pathway dysregulation, was shown to correlate with impaired G, phase DNMT1 destruction and RB inactivation by hyperphosphorylation in several normal and cancer cell lines. Furthermore, in a series of 85 cases of human breast cancer, a moderately strong, but highly significant, correlation between MAD2 and DNMT1 immunohistochemical staining was observed, yielding a Spearman rank order correlation coefficient of 0.37 (P <0.001). This suggests that RB pathway inactivation, a common dysfunction in cancer cells, may be the underlying cause of DNMT1 dysregulation.",
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AU - Nelson, William G

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