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J. Biol. Chem., Vol. 281, Issue 34, 24790-24802, August 25, 2006

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Tumor Suppressor p16^INK4A Regulates Polycomb-mediated DNA Hypermethylation in Human Mammary Epithelial Cells^*

Paul A. Reynolds, Mahvash Sigaroudinia, Giuseppe Zardo^¶, Matthew B. Wilson, Geoffrey M. Benton, Caroline J. Miller, Chibo Hong^¶, Jane Fridlyand, Joseph F. Costello^¶, and Thea D. Tlsty¹

From the Comprehensive Cancer Center, the Department of Pathology, and ^¶Brain Tumor Research Center and Department of Neurological Surgery, University of California, San Francisco, San Francisco, California 94143-0511

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 up-regulated 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 p16^INK4A 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.

Received for publication, May 2, 2006 , and in revised form, June 7, 2006.

^* This work was supported by National Institutes of Health R01 Grant CA97214 (to T. D. T.), a SPORE P50 Grant CA58207 (to T. D. T.), an AVON Scholar Award, and a Department of Defense Concept Award. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4.

¹ To whom correspondence should be addressed: Dept. of Pathology, University of California San Francisco, 513 Parnassus Ave. HSW501, San Francisco, CA 94143-0511. Tel.: 415-502-6115; Fax: 415-502-6163; E-mail: thea.tlsty{at}ucsf.edu.

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