Polycomb CBX7 promotes initiation of heritable repression of genes frequently silenced with cancer-specific DNA hypermethylation.
Epigenetic silencing of genes in association with aberrant promoter DNA hypermethylation has emerged as a significant mechanism in the development of human cancers. Such genes are also often targets of the polycomb group repressive complexes in embryonic cells. The polycomb repressive complex 2 (PRC2) has been best studied in this regard. We now examine a link between PRC1 and cancer-specific gene silencing. Here, we show a novel and direct association between a constituent of the PRC1 complex, CBX7, with gene repression and promoter DNA hypermethylation of genes frequently silenced in cancer. CBX7 is able to complex with DNA methyltransferase (DNMT) enzymes, leading us to explore a role for CBX7 in maintenance and initiation of gene silencing. Knockdown of CBX7 was unable to relieve suppression of deeply silenced genes in cancer cells; however, in embryonal carcinoma (EC) cells, CBX7 can initiate stable repression of genes that are frequently silenced in adult cancers. Furthermore, we are able to observe assembly of DNMTs at CBX7 target gene promoters. Sustained expression of CBX7 in EC cells confers a growth advantage and resistance to retinoic acid-induced differentiation. In this setting, especially, there is increased promoter DNA hypermethylation for many genes by analysis of specific genes, as well as through epigenomic studies. Our results allow us to propose a potential mechanism through assembly of novel repressive complexes, by which the polycomb component of PRC1 can promote the initiation of epigenetic changes involving abnormal DNA hypermethylation of genes frequently silenced in adult cancers.
Mohammad
Helai P
HP
The Sidney Kimmel Comprehensive Cancer Institute at Johns Hopkins, Baltimore, Maryland 21231, USA.
Cai
Yi
Y
McGarvey
Kelly M
KM
Easwaran
Hariharan
H
Van Neste
Leander
L
Ohm
Joyce E
JE
O'Hagan
Heather M
HM
Baylin
Stephen B
SB
D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D063150:Polycomb Repressive Complex 1; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology; D000097584:DNA Methyltransferase 3B
D000970:Antineoplastic Agents; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D063150:Polycomb Repressive Complex 1; D012097:Repressor Proteins; D014212:Tretinoin; D000097584:DNA Methyltransferase 3B; C503627:CBX7 protein, human; C000717967:DNMT3A protein, human