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

Reynolds, Paul A.; Sigaroudinia, Mahvash; Zardo, Giuseppe; Wilson, Mark; Benton, Geoffrey Marsing; Miller, Caroline; Hong, Chibo; Fridlyand, Jane; Costello, J; Tlsty, Thea D.

doi:10.1074/jbc.m604175200

Cited by 123 publications

(103 citation statements)

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“…EZH2 expression is increased in tumors of different histological types, including precancerous tissues (42,43). The Polycomb component EZH2 associates with DNA methyltransferase activity and can promote DNA hypermethylation (44)(45)(46), and a speculative mechanism can be proposed that links Polycomb silencing with tumor-associated DNA methylation. This mechanistic link has received support from recent studies finding good concordance between Polycomb occupancy of genes in noncancerous cells and tissues including ES cells with cancer-associated DNA hypermethylation events (47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay

Rauch¹,

Wang²,

Zhang³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

260

221

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De novo methylation of CpG islands is a common phenomenon in human cancer, but the mechanisms of cancer-associated DNA methylation are not known. We have used tiling arrays in combination with the methylated CpG island recovery assay to investigate methylation of CpG islands genome-wide and at high resolution. We find that all four HOX gene clusters on chromosomes 2, 7, 12, and 17 are preferential targets for DNA methylation in cancer cell lines and in early-stage lung cancer. CpG islands associated with many other homeobox genes, such as SIX, LHX, PAX, DLX, and Engrailed, were highly methylated as well. Altogether, more than half (104 of 192) of all CpG island-associated homeobox genes in the lung cancer cell line A549 were methylated. Analysis of paralogous HOX genes showed that not all paralogues undergo cancerassociated methylation simultaneously. The HOXA cluster was analyzed in greater detail. Comparison with ENCODE-derived data shows that lack of methylation at CpG-rich sequences correlates with presence of the active chromatin mark, histone H3 lysine-4 methylation in the HOXA region. Methylation analysis of HOXA genes in primary squamous cell carcinomas of the lung led to the identification of the HOXA7-and HOXA9-associated CpG islands as frequent methylation targets in stage 1 tumors. Homeobox genes are potentially useful as DNA methylation markers for early diagnosis of the disease. The finding of widespread methylation of homeobox genes lends support to the hypothesis that a substantial fraction of genes methylated in human cancer are targets of the Polycomb complex.DNA methylation ͉ HOX genes ͉ chromatin ͉ Polycomb

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Section: Discussionmentioning

confidence: 99%

Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay

Rauch¹,

Wang²,

Zhang³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

260

221

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“…Epigenetic systems that dictate chromatin structure are regulated by pRb, most often through the downstream regulation of transcriptional targets that activate histone methyltransferases, DNA methyltransferases, or acetylases. The repression of p16 activity, accompanied by the inactivation of pRb as a transcriptional repressor, leads to the overexpression of chromatin-remodeling proteins such as EZH2 and SUZ12 (47,48). In addition to executing the silencing of selected loci, overexpression of these proteins has been identified in approximately half of DCIS lesions and indicate a poor prognosis when detected in invasive breast cancers (49,50).…”

Section: Deregulated P16/prb Signaling: Phenotypic Consequences For Dcismentioning

confidence: 99%

Premalignant Breast Neoplasia: A Paradigm of Interlesional and Intralesional Molecular Heterogeneity and Its Biological and Clinical Ramifications

Berman

Gauthier

Tlsty

2010

Cancer Prevention Research

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As is well established in invasive breast disease, it is becoming increasingly clear that molecular heterogeneity, both between and within lesions, is a prevalent, distinct phenotype of premalignant lesions of the breast. Key pathways of tumorigenesis modulate critical features of premalignant lesions such as proliferation, differentiation, stress response, and even the generation of diversity. Current studies show that evaluation of these lesions may provide clinically useful information on future tumor formation as well as biological insights into the origin and functional significance of this distinct phenotype. Cancer Prev Res; 3(5); 579-87. ©2010 AACR.

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“…We recently reported that the repression of p16 INK4A in primary human mammary epithelial cells (HMEC) activates an E2F-mediated increase in proteins that remodel chromatin and causes targeted de novo DNA methylation at a non-random collection of loci (1). These studies show that cells can acquire epigenetic plasticity by altering the p16/pRb pathway, and that this program of acquired de novo methylation has a deterministic (predictable) rather than stochastic (random) pattern.…”

mentioning

confidence: 97%

Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers

Dumont

Wilson

Crawford

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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193

172

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The active acquisition of epigenetic changes is a poorly understood but important process in development, differentiation, and disease. Our work has shown that repression of the p16/pRb pathway in human epithelial cells, a condition common to stem cells and many tumor cells, induces dynamic epigenetic remodeling resulting in the targeted methylation of a selected group of CpG islands. We hypothesized that cells in this epigenetically plastic state could be programmed by the microenvironment to acquire epigenetic changes associated with tumorigenesis. Here, we describe an in vitro model system where epigenetically plastic cells were placed in an environment that induced epithelial to mesenchymal transition (EMT) and led to a program of acquired de novo DNA methylation at targeted sites. In this model, we found that repression of E-cadherin transcription preceded the subsequent acquisition of methylated CpG sites. Furthermore, the induction of EMT was accompanied by de novo methylation of several other gene promoters, including those of the estrogen receptor and Twist. These data demonstrate that signals from the microenvironment can induce phenotypic and gene expression changes associated with targeted de novo epigenetic alterations important in tumor progression, and that these alterations occur through a deterministic, rather than stochastic, mechanism. Given the dynamic epigenetic reprogramming that occurs in these cells, DNA methylation profiles observed in human tumors may reflect the history of environmental exposures during the genesis of a tumor.epigenetic remodeling ͉ human mammary epithelial cells ͉ microenvironment ͉ ras T he heritable regulation of gene expression changes that are critical to processes such as differentiation and disease can be controlled by epigenetic modifications of proteins and DNA sequences. We recently reported that the repression of p16 INK4A in primary human mammary epithelial cells (HMEC) activates an E2F-mediated increase in proteins that remodel chromatin and causes targeted de novo DNA methylation at a non-random collection of loci (1). These studies show that cells can acquire epigenetic plasticity by altering the p16/pRb pathway, and that this program of acquired de novo methylation has a deterministic (predictable) rather than stochastic (random) pattern. Furthermore, the coordinated set of de novo DNA methylation events are preceded by, and dependent upon, the repression of gene expression. Thus, during cancer progression, one may envision that tumor cells can acquire epigenetic plasticity through repression of the p16/pRb pathway via mutations, deletions, or methylation (2), which then provides the potential for programming epigenetic events. These observations are reminiscent of studies that show the acquisition of promoter hypermethylation upon modulation of estrogen or retinoic acid signaling (3, 4). In these cell population-based studies it is unclear whether the nonrandom hypermethylation events observed are due to induction or selection. To explore this question...

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

Cited by 123 publications

References 50 publications

Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay

Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay

Premalignant Breast Neoplasia: A Paradigm of Interlesional and Intralesional Molecular Heterogeneity and Its Biological and Clinical Ramifications

Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers

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