Epigenetic silencing of the RASSF1A tumor suppressor gene through HOXB3-mediated induction of DNMT3B expression
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Authors
Palakurthy, Rajendra KumarWajapeyee, Narendra
Santra, Manas K.
Gazin, Claude
Lin, Ling
Gobeil, Stephane
Green, Michael R.
Document Type
Journal ArticlePublication Date
2009-10-27Keywords
AnimalsCell Line, Tumor
Cell Proliferation
DNA (Cytosine-5-)-Methyltransferase
Down-Regulation
Gene Expression Regulation, Neoplastic
*Gene Silencing
Genome, Human
Homeodomain Proteins
Humans
Lung Neoplasms
Mice
Promoter Regions, Genetic
Protein Binding
RNA, Small Interfering
Repressor Proteins
Tumor Suppressor Proteins
Genetics and Genomics
Metadata
Show full item recordAbstract
The RASSF1A tumor suppressor gene is epigenetically silenced in a variety of cancers. Here, we perform a genome-wide human shRNA screen and find that epigenetic silencing of RASSF1A requires the homeobox protein HOXB3. We show that HOXB3 binds to the DNA methyltransferase DNMT3B gene and increases its expression. DNMT3B, in turn, is recruited to the RASSF1A promoter, resulting in hypermethylation and silencing of RASSF1A expression. DNMT3B recruitment is facilitated through interactions with Polycomb repressor complex 2 and MYC, which is bound to the RASSF1A promoter. Mouse xenograft experiments indicate that the oncogenic activity of HOXB3 is due, at least in part, to epigenetic silencing of RASSF1A. Expression analysis in human lung adenocarcinoma samples reveals that RASSF1A silencing strongly correlates with overexpression of HOXB3 and DNMT3B. Analysis of human cancer cell lines indicates that the RASSF1A epigenetic silencing mechanism described here may be common in diverse cancer types.Source
Mol Cell. 2009 Oct 23;36(2):219-30. Link to article on publisher's siteDOI
10.1016/j.molcel.2009.10.009Permanent Link to this Item
http://hdl.handle.net/20.500.14038/44099PubMed ID
19854132Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.molcel.2009.10.009