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Chromosomal autonomy of hMLH1 methylation in colon cancer

Oncogene volume 21, pages 1443–1449 (2002)Cite this article

Abstract

Silencing of hMLH1 expression by aberrant hMLH1 promoter methylation accounts for the majority of sporadic colon cancers with microsatellite instability. We have previously shown hMLH1 silencing is biallelic and actively maintained. To study the mechanism of aberrant hMLH1 methylation, we assayed whether an hMLH1 methylated cell could transfer methylation and silencing to an exogenous hMLH1 promoter in somatic cell hybrids between hMLH1 methylated-silenced and hMLH1 unmethylated-expressing colon cancer cells. Conversely, we assayed whether these hybrids could reactivate expression of initially methylated and silenced hMLH1 alleles. Compellingly, within the hybrids each hMLH1 allele remained unchanged, retaining the expression status of its parental cell of origin. This chromosomal autonomy may not be simply determined by DNA methylation, as it is reasserted after experimentally forced demethylation of all hMLH1 alleles in the hybrids. Confirming findings included hMLH1 methylated cells being unable to methylate single transferred exogenous hMLH1 expressing chromosomes or transfected hMLH1 reporter constructs. hMLH1 silencing does not conform to either a dominant or recessive model, and is not determined by trans-acting factors differing between hMLH1 expressing or silenced genomes. We posit that hMLH1 methylation is dependent on and maintained by cis chromosomal marks, whose nature remains to be elucidated.

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Acknowledgements

We thank Song Song for her technical assistance. The work is supported by PHS grants RO1 CA67409, RO1 CA72160 and P30 CA43703, and by gifts from the National Colon Cancer Research Alliance. S Markowitz is an associate investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Microbiology and Molecular Biology, Case Western Reserve University, Cleveland, 44106, Ohio, OH, USA

    Hui Li & Sanford Markowitz

  2. Cancer Center and Department of Medicine at Case Western Reserve University, Cleveland, 44106, Ohio, OH, USA

    Hui Li, Lois Myeroff, James KV Willson & Sanford Markowitz

  3. Department of Medicine, Ireland Cancer Center and Research Institute at University Hospitals of Cleveland, Cleveland, 44106, Ohio, OH, USA

    Hui Li, Lois Myeroff & Sanford Markowitz

  4. Howard Hughes Medical Institute, Cleveland, Ohio, OH, 44106, USA

    Lakshmi Kasturi & Sanford Markowitz

  5. Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, 44195, Ohio, OH, USA

    Lisa Krumroy & Graham Casey

  6. Department of Genetics, Case Western Reserve University and Research Institute at University Hospitals of Cleveland, Cleveland, 44106, Ohio, OH, USA

    Stuart Schwartz

  7. University of California Irvine, Irvine, 92697, California, CA, USA

    Eric Stanbridge

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  1. Hui Li
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Correspondence to Sanford Markowitz.

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Li, H., Myeroff, L., Kasturi, L. et al. Chromosomal autonomy of hMLH1 methylation in colon cancer. Oncogene 21, 1443–1449 (2002). https://doi.org/10.1038/sj.onc.1205247

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