title: Tumor suppressor p16INK4A regulates polycomb-mediated DNA hypermethylation in human mammary epithelial cells.
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 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.
authors.affiliation: Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143-0511, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Reynolds
authors.forename: Mahvash
authors.initials: M
authors.lastname: Sigaroudinia
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zardo
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Wilson
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Benton
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Miller
authors.forename: Chibo
authors.initials: C
authors.lastname: Hong
authors.forename: Jane
authors.initials: J
authors.lastname: Fridlyand
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Costello
authors.forename: Thea D
authors.initials: TD
authors.lastname: Tlsty
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; C097899:homeobox protein HOXA9; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2