Skip to content

Research at St Andrews

Tumour Suppressor p16INK4A Regulates Polycomb-mediated DNA Hypermethylation in Human Mammary Epithelial Cells

Research output: Contribution to journalArticle

DOI

Author(s)

Paul Andrew Reynolds, M Sigaroudinia, G Zardo, MB Wilson, G Benton, C Miller, C Hong, J Fridlyand, JF Costello, TD Tlsty

School/Research organisations

Abstract

Alterations in DNA methylation are important in cancer, but the acquisition of these alterations is poorly understood. Using an unbiased global screen for CpG island methylation events, we have identified a non-random pattern of DNA hypermethylation acquired in p16-repressed cells. Interestingly, this pattern included loci located upstream of a number of homeobox genes. Upon removal of p16(INK4A) activity in primary human mammary epithelial cells, polycomb repressors, EZH2 and SUZ12, are upregulated and recruited to HOXA9, a locus expressed during normal breast development and epigenetically silenced in breast cancer. We demonstrate that at this targeted locus, the up-regulation of polycomb repressors is accompanied by the recruitment of DNA methyltransferases and the hypermethylation of DNA, an endpoint, which we show to be dependent on SUZ12 expression. These results demonstrate a causal role of p16INK4A disruption in modulating DNA hypermethylation, and identify a dynamic and active process whereby epigenetic modulation of gene expression is activated as an early event in breast tumor progression.

Close

Details

Original languageEnglish
Pages (from-to)24790-24802
Number of pages13
JournalJournal of Biological Chemistry
Volume281
Issue number34
DOIs
Publication statusPublished - 25 Aug 2006

    Research areas

  • CPG-ISLAND METHYLATION, GROUP PROTEIN EZH2, PROMOTER HYPERMETHYLATION, P16 EXPRESSION, BREAST-CANCER, SELF-RENEWAL, GENE, SENESCENCE, GROWTH, CHROMATIN

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Genome-scale CRISPR/Cas9 screen determines factors modulating sensitivity to ProTide NUC-1031

    Sarr, A., Bré, J., Um, I. H., Chan, T. H., Mullen, P., Harrison, D. J. & Reynolds, P. A., 21 May 2019, In : Scientific Reports. 9, 13 p., 7643.

    Research output: Contribution to journalArticle

  2. Glutaminase inhibition in renal cell carcinoma therapy

    Raczka, A. M. & Reynolds, P. A., 14 May 2019, In : Cancer Drug Resistance. 2, 9 p.

    Research output: Contribution to journalReview article

  3. Podocyte injury elicits loss and recovery of cellular forces

    Haley, K., Kronenberg, N. M., Liehm, P., Elshani, M., Bell, C., Harrison, D. J., Gather, M. C. & Reynolds, P. A., 27 Jun 2018, In : Science Advances. 4, 6, 9 p., eaap8030.

    Research output: Contribution to journalArticle

  4. Crumbs 3b promotes tight junctions in an ezrin-dependent manner in mammalian cells

    Tilston-Lunel, A. M., Haley, K., Schlecht, N., Wang, Y., Chatterton, A. L. D., Moleirinho, S. L., Watson, A., Hundal, H., Prystowsky, M., Gunn-Moore, F. J. & Reynolds, P. A., Oct 2016, In : Journal of Molecular Cell Biology. 8, 5, p. 439-455

    Research output: Contribution to journalArticle

  5. Willing to be involved in cancer

    Gunn-Moore, F. J., Tilston-Lunel, A. M. & Reynolds, P. A., 18 Jul 2016, In : Genes. 7, 7, 13 p., 37.

    Research output: Contribution to journalReview article

Related by journal

  1. Journal of Biological Chemistry (Journal)

    Simon John Powis (Member of editorial board)
    1 Jun 2015

    Activity: Publication peer-review and editorial work typesEditor of research journal

  2. Journal of Biological Chemistry (Journal)

    Terry K Smith (Member of editorial board)
    2006 → …

    Activity: Publication peer-review and editorial work typesPeer review of manuscripts

Related by journal

  1. Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage

    Reilly-O'Donnell, B., Robertson, G. B., Karumbi, A., McIntyre, C., Bal, W., Nishi, M., Takeshima, H., Stewart, A. J. & Pitt, S. J., 11 Aug 2017, In : Journal of Biological Chemistry. 292, 32, p. 13361-13373 13 p.

    Research output: Contribution to journalArticle

  2. The major histocompatibility complex class I immunopeptidome of extracellular vesicles

    Synowsky, S. A., Shirran, S. L., Cooke, F. G. M., Antoniou, A. N., Botting, C. H. & Powis, S. J., 13 Oct 2017, In : Journal of Biological Chemistry. 292, p. 17084-17092

    Research output: Contribution to journalArticle

  3. Response to Qian and Colvin: zinc-mediated regulation of the cardiac ryanodine receptor occurs via multiple binding sites

    Woodier, J., Rainbow, R. D., Stewart, A. J. & Pitt, S. J., 19 Feb 2016, In : Journal of Biological Chemistry. 291, 8, p. 4267

    Research output: Contribution to journalLetter

  4. Using a genetically encoded sensor to identify inhibitors of Toxoplasma gondii Ca2+ Signalling

    Sidik, S. M., Hortua Triana, M. A., Paul, A. S., El Bakkouri, M., Hackett, C. G., Tran, F., Westwood, N. J., Hui, R., Zuercher, W. J., Duraisingh, M. T., Moreno, S. N. J. & Lourido, S., 29 Apr 2016, In : Journal of Biological Chemistry. 291, 18, p. 9566-9580 15 p.

    Research output: Contribution to journalArticle

  5. Streptococcus pneumoniae NanC. Structural insights into the specificity and mechanism of a sialidase that produces a sialidase inhibitor

    Owen, C. D., Lukacik, P., Potter, J. A., Sleator, O., Taylor, G. L. & Walsh, M. A., 13 Nov 2015, In : Journal of Biological Chemistry. 290, 46, p. 27736-27748 13 p.

    Research output: Contribution to journalArticle

ID: 383036

Top